Fused pyrrole compounds, pharmaceutical agents containing the same, and the use thereof

ABSTRACT

The present invention relates to fused pyrrole compounds of the formula 1.  
                 
 
     in which at least one of the radicals R1, R2, R3 is 4-sulphur-substituted phenyl.  
     These compounds are in particular pyrrolizines, indolizines and heteroanalogues having selective inhibitory action on isoenzyme-2 of prostaglandin H synthase (COX-2). The invention also relates to pharmaceutical compositions which contain these compounds; and the use of these compounds for the treatment of disorders of the rheumatic type.

[0001] The present invention relates to fused pyrrole compounds, inparticular pyrrolizines, indolizines and heteroanalogues havingselective inhibitory action on isoenzyme-2 of prostaglandin H synthase(COX-2); pharmaceutical compositions which contain these compounds; andthe use of these compounds for the treatment of disorders of therheumatic type.

[0002] It is recognized that the arachidonic acid metabolitesprostaglandin E₂ (PGE₂), prostaglandin 12 (PGI₂) and thromboxane B₂(TXB₂) intervene profoundly in the inflammatory process. The key enzymefor prostaglandin synthesis is prostaglandin H synthase. As acyclooxygenase, it produces prostaglandin H₂ (PGH₂) from arachidonicacid via the intermediate prostaglandin G₂ (PGG₂). The enzyme exists intwo isoforms, namely cyclooxygenase-1 and cyclooxygenase-2. Since thestructures of the two isoezymes have already been elucidated, structuraldifferences between the two enzymes have also been investigated morethoroughly.

[0003] Cyclooxygenase-1 exists in almost all cells and produces intra-and extracellular ubiquitous prostaglandin mediators which are necessaryin physiological amounts for the function of organs, such as the stomachand kidneys.

[0004] The inhibition of this enzyme suppresses the synthesis of thevasodilating PGE₂ as well as that of the cytoprotective PGI₂. Thedecreased circulation and lack of protective effect can lead to damageto the gastric mucous membrane and as a result to ulceration. As aresult of ischaemia, decreased renal blood flow can lead to damage tothe renal parenchyma and further to renal insufficiency.

[0005] Cyclooxygenase-2, however, is only found in specialized cells,e.g. in blood cells, such as monocytes and granulocytes, in synovialcells, vascular endothelial cells (venous) and locally in inflamedtissue. Experimentally, the formation (expression) of the isoenzyme-2 isinduced by phorbol esters, lipopolysaccharides and other stress factorswhich can provoke local inflammation.

[0006] Non-steroidal anti-inflammatory drugs (NSAIDs), such asacetylsalicylic acid, mefanamic acid, diclofenac, indomethacin,ibuprofen and naproxen, are widely used clinically. Pharmacologically,they act via inhibition of cyclooxygenase.

[0007] Pyrrolizine compounds which have a similar pharmacological actionare known from numerous publications. For example, pyrrolizine compoundshaving anti-inflammatory activity are described in Arch. Pharm. 319,65-69 (1986); 319, 231-234 (1986); 318, 661-663 (1985); 318, 663-664(1985); 319, 500-505 (1986); 319, 749-755 (1986); 327, 509-514 (1994);330, 307-312 (1997) and in J. Med. Chem. 1987, 30, 820-823 and 1994, 37,1894-1897.

[0008] Further pyrrolizine compounds are described in U.S. Pat. No.5,260,451 (corresponding to EP 0397175) and in WO 95/32970; WO 95/32971;and WO 95/32972. These compounds have the structural formula

[0009] A fused diarylpyrrole structural element and a third acidicradical R³ is common to all compounds. The compounds are distinguishedby high lipophilicity, good bioavailability and average half-lives, seeDrugs of the Future, 1995, 20 (10):1007-1009.

[0010] Further pyrrolizine compounds of similar constitution aredescribed in DE 198 45 446.6 and PCT/EP 99/09057. According to U.S. Pat.No. 4,232,038, alkylsulphinylbenzoyl- andalkylsulphonylbenzoyl-substituted pyrrolizines should also haveanti-inflammatory, analgesic and antipyretic properties. According to DE196 24 290.8 and DE 196 24 289.4, certain compounds of this type havelipid-lowering action.

[0011] ML 3000 (1), for example, a vicinally diaryl-substituted pyrrolederivative, is described as a dual inhibitor of cyclooxygenase (COX) and5-lipoxygenase (LOX).

[0012] However, via the inhibition of cyclooxygenase, toxic side effectsalso result, which are especially associated with the inhibition of theconstitutive, physiological cyclooxygenase-1. More recent investigationsshow that the classical NSAIDs have an inadequate selectivity andfrequently even prefer the isoenzyme-1 of cyclooxygenase.

[0013] A selective inhibition of the cyclooxygenase-2 specificallyoverexpressed in inflamed tissue and leading to tissue damage due to theformation of non-physiological tissue levels of prostaglandins shouldlead to a superior, namely lower side-effect, anti-inflammatoryprinciple.

[0014] Substances which selectively inhibit cyclooxygenase-2 havelikewise already been described.

[0015] These especially include all 5-membered heterocyclic rings havingbisaryl substitution. For example, WO 94/15932 mentions3,4-diarylthiophenes, -furans and -pyrroles, and occasionally3-(4-methylsulphonylphenyl)₄-(4-fluorophenyl)thiophene. WO 94/27980describes 4,5-diaryloxazoles, for example4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulphonyl)phenyl]oxazole. In EP0087629, 2,3-diaryl-5-halothiophenes, for example5-bromo-2,3-bis(4-fluorophenyl)thiophene, are mentioned and WO 95/15315reports 1,5-diphenylpyrazoles, for example5-(4-fluorophenyl)-1-[4-(methylsulphonyl)phenyl]-3-(trifluoromethyl)pyrazole.2,3-Diarylpyrroles are mentioned in WO 95/00501 just as the3,4-diarylfuranones illustrated below by example of lactones 4 and 5.

[0016] In addition, cycloaliphatic or aromatic non-heterocyclic ringswith bisaryl substitution are also found. For example, bisarylphenyls,for example 2-[(4-methylthio)phenyl]-1-biphenyl, are also described inWO 96/10012. 5-membered rings, in turn, can be looked up in WO 95/11883as 1,2-diarylcyclopentenes illustrated below by example of thecyclopentene 6, (SC57666, SC 57949), and to which a spiro unit can belinked in the 4-position following WO 95/21817, for example as is thecase in5-(4-fluorophenyl)-6-[4-(methylsulphonyl)phenyl]spiro[2.4]hept-5-ene.Finally, the 2,3-diarylcyclopentadienes described in WO 95/30656, forexample1-methylsulphonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene,may also be mentioned.

[0017] Further pyrroles are described by Wilkerson et al. in J. Med.Chem 1994, 37, 988-998 and J. Med. Chem. 1995, 38, 3895-3901. WO99/61016 also indicates certain substituted pyrroles as cyclooxygenase-2inhibitors.

[0018] In the case of the lactones 4 and 5, only compound 5 shows a highactivity on cyclooxygenase-2 and high selectivity for this isoform.

[0019] The object of the present invention was to make available novelcompounds which inhibit cyclooxygenase-2 more strongly thancyclooxygenase-1.

[0020] This object has surprisingly been achieved by means of [α]-fusedpyrrole compounds which carry a phenyl group substituted in thepara-position by certain sulphur-containing groups.

[0021] The present invention therefore relates to [(]-fused pyrrolecompounds of the formula 1

[0022] in which

[0023] X is CR8R9, S, O, NR12 or C(O);

[0024] A is CR10R11 or a bond between X and the atom carrying theradicals R6 and R7;

[0025] the first of the radicals R1, R2, R3 is

[0026] 4-substituted phenyl, the substituent being selected fromalkylthio, alkylsulphinyl, alkylsulphonyl, sulphamoyl,N-alkylsulphamoyl, N,N-dialkylsulphamoyl, alkylsulphonamido oralkylsulphone-N-alkylamido;

[0027] the second of the radicals R1, R2, R3 is

[0028] alkyl which is optionally substituted by identical or differentsubstituents selected from halogen, cycloalkyl, alkoxy,trifluoromethoxy, hydroxyl or trifluoromethyl,

[0029] cycloalkyl which is optionally substituted by identical ordifferent substituents selected from halogen, alkyl, haloalkyl,cycloalkyl, alkoxy, haloalkoxy or hydroxyl,

[0030] phenyl which is optionally substituted by identical or differentsubstituents selected from halogen, alkyl, haloalkyl, alkoxy,haloalkoxy, alkylthio, hydroxyl, nitro, alkylsulphinyl, alkylsulphonyl,sulphamoyl, N-alkylsulphamoyl, N,N-dialkylsulphamoyl, alkylsulphonamidoor alkylsulphone-N-alkylamido; or

[0031] an aromatic or non-aromatic mono- or bicyclic, optionallybenzo-fused, heterocyclic radical which contains 1, 2 or 3 heteroatomsindependently of one another selected from N, O and S and is optionallysubstituted by identical or different substituents selected fromhalogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxyl,nitro, alkylsulphinyl, alkylsulphonyl, sulphamoyl, N-alkylsulphamoyl,N,N-dialkylsulphamoyl, alkylsulphonamido or alkylsulphone-N-alkylamido;

[0032] the third of the radicals R1, R2, R3 is

[0033] H, alkyl, haloalkyl, hydroxyalkyl, —CHO, —COOH, —COCOOH,—COO-alkyl, —COO-Alkphenyl, —COCOO-alkyl, halogen, cyano,alkylsulphonyl, sulphamoyl or B—Y;

[0034] in which

[0035] B is alkylene or alkyenylene, each of which can optionally besubstituted by hydroxyl or alkoxy;

[0036] Y is —COOH, —COO-alkyl, —SO₃-alkyl, —CHO or hydroxyl; or

[0037] the second and the third of the radicals R1, R2, R3, togetherwith the C atoms to which they are bonded, are saturated or unsaturatedcycloalkyl;

[0038] R4-R11, which can be identical or different, are hydrogen, alkyl,hydroxyalkyl, alkoxyalkyl, hydroxyl, COOH or acyloxy, where vicinalradicals can also represent bonds or geminal radicals, also togetherwith the C atom to which they are bonded, can represent carbonyl orcycloalkyl;

[0039] R12 is hydrogen, alkyl or phenyl,

[0040] and optical isomers, physiologically tolerable salts andphysiologically hydrolysable esters thereof.

[0041] Preferred embodiments to which this invention relates aredescribed in the adjacent claims.

[0042] The physiologically tolerable salts in the present case can beacid addition or base addition salts.

[0043] For acid addition salts, inorganic acids, such as hydrochloricacid, sulphuric acid, nitric acid or phosphoric acid, or organic acids,in particular carboxylic acids, e.g. acetic acid, tartaric acid, lacticacid, citric acid, malic acid, mandelic acid, ascorbic acid, maleicacid, fumaric acid, gluconic acid or sulphonic acids, e.g.methanesulphonic acid, benzenesulphonic acid and toluenesulphonic acid,and the like are used.

[0044] The base addition salts include salts of the compounds of theformula I with inorganic bases, such as sodium hydroxide or potassiumhydroxide, or with organic bases, such as mono-, di- or triethanolamine.

[0045] Physiologically easily hydrolysable esters of the compounds ofthe formula I are, for example, alkyl, pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl esters.

[0046] If the compounds according to the invention have asymmetriccentres, racemates and optical isomers are included as mixtures or inpure form (enantiomers, diastereomers).

[0047] The term “alkyl, alkoxy etc.” includes straight-chain or branchedalkyl groups, such as CH₃, C₂H₅, n-propyl, CH(CH₃)₂, n-butyl,CH(CH₃)—C₂H₅, isobutyl, C(CH₃)₃, n-pentyl or n-hexyl, in particular CH₃,C₂H₅ or CH(CH₃)₂, preferably having—if not stated otherwise—1 to 8, inparticular 1 to 6 and particularly preferably 1 to 4, carbon atoms; as asubstituent of one of the radicals R1 to R12, “alkyl, alkoxy etc.”preferably comprises 1 to 4 carbon atoms.

[0048] Substituted “alkyl, alkoxy etc.” in particular includes:

[0049] haloalkyl, i.e. alkyl which is partially or completelysubstituted by fluorine, chlorine, bromine and/or iodine, i.e., forexample, CH₂F, CHF₂, CF₃, CH₂Cl, 2-fluoroethyl, 2-chloroethyl or2,2,2-trifluoroethyl; as a substituent of one of the radicals R1 to R12,haloalkyl is preferably CHF₂ and especially CF₃;

[0050] haloalkoxy, i.e. alkoxy which is partially or completelysubstituted by fluorine, chlorine, bromine and/or iodine, i.e., forexample, the haloalkoxy radicals corresponding to the haloalkyl radicalslisted above; as a substituent of one of the radicals R1 to R12,haloalkoxy is preferably OCHF₂ and especially OCF₃;

[0051] alkoxyalkyl, i.e. alkyl substituted by alkoxy, i.e., for example,—CH₂—OCH₃ or 2-methoxyethyl;

[0052] hydroxyalkyl, i.e. alkyl which is preferably monosubstituted byhydroxyl, e.g. hydroxymethyl or 2-hydroxyethyl;

[0053] trifluoromethylalkyl, i.e. alkyl which is preferablymonosubstituted by trifluoromethyl, e.g. the radicals described underhydroxyalkyl, which are substituted by trifluoromethyl instead of byhydroxyl;

[0054] trifluoromethoxyalkyl, i.e. alkyl which is preferablymonosubstituted by trifluoromethoxy, e.g. the radicals described underhydroxyalkyl which are substituted by trifluoromethoxy instead of byhydroxyl;

[0055] cycloalkylalkyl, i.e. alkyl which is preferably monosubstitutedby cycloalkyl, e.g. the radicals described under hydroxyalkyl, which aresubstituted by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexylinstead of by hydroxyl.

[0056] The term “cycloalkyl” includes mono- or bicyclic alkyl groups,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.,preferably having—if not stated otherwise—3 to 9, in particular 3 to 7and particularly preferably 5 or 6, carbon atoms.

[0057] The term “alkylene” includes straight-chain or branched alkylenegroups, such as methylene and ethylene, preferably having—if not statedotherwise—1 to 8, in particular 1 to 6 and particularly preferably 1 to4, carbon atoms. If alkylene is substituted by hydroxyl or alkoxy,monosubstitution is preferred.

[0058] The term “alkenylene” includes straight-chain or branched, mono-or polyunsaturated alkylene groups, such as ethenylene, preferablyhaving—if not stated otherwise—2 to 8, in particular 2 to 6 andparticularly preferably 2 to 4, carbon atoms. If alkenylene issubstituted by hydroxyl or alkoxy, monosubstitution is preferred.

[0059] Acyloxy means —OCOR, in which R can be alkyl or aryl. Acetyloxyand benzoyloxy may be mentioned in particular.

[0060] —COOAlkyl means alkoxycarbonyl, such as CO—OCH₃, CO—OC₂H₅,CO—OCH₂—C₂H₅, CO—OCH(CH₃)₂, n-butoxycarbonyl, CO—OCH(CH₃)—C₂H₅,CO—OCH₂—CH(CH₃)₂, CO—OC(CH₃)₃, in particular CO—OCH₃, CO—OC₂H₅,CO—OCH(CH₃)₂ or CO—OCH₂—CH(CH₃)₂.

[0061] —COOAlkPhenyl means an alkoxycarbonyl group substituted by phenylon the alkyl radical, such as benzyloxycarbonyl.

[0062] —COCOOAlkyl means an alkyl ester of a carboxycarbonyl group.

[0063] Alkylthio means —S-alkyl and is also designated as alkylsulphanylor alkylmercapto, such as SCH₃, SC₂Hs, SCH₂—C₂H₅, SCH(CH₃)₂,n-butylthio, 1-methylpropylthio, 2-methylpropylthio, SC(CH₃)₃.Methylthio is preferred.

[0064] Alkylsulphinyl means —S(O)-alkyl and is also designated asalkylsulphoxo, such as SO—CH₃, SO—C₂H₅, n-propylsulphinyl,1-methylethylsulphinyl, n-butylsulphinyl, 1-methylpropylsulphinyl,2-methylpropylsulphinyl, 1,1-dimethylethylsulphinyl. Methylsulphinyl ispreferred.

[0065] Alkylsulphonyl means —S(O)₂-alkyl and is also designated asalkylsulphone, such as SO₂—CH₃, SO₂—C₂H₅, n-propylsulphonyl,SO₂—CH(CH₃)₂, n-butylsulphonyl, 1-methylpropylsulphonyl,2-methylpropylsulphonyl, SO₂—C(CH₃)₃. Methylsulphonyl is preferred.

[0066] Sulphamoyl means —S(O)₂NH₂ and is also designated asamidosulphonyl or sulphonamide.

[0067] N-Alkylsulphamoyl means monosubstituted sulphamoyl—S(O)₂NH-alkyl, e.g. —S(O)₂NH—CH₃.

[0068] N,N-Dialkylsulphamoyl means disubstituted sulphamoyl—S(O)₂N-(alkyl)₂, where the two nitrogen-bonded alkyl radicals can beidentical or different, e.g. —S(O)₂N(CH₃)₂.

[0069] Alkylsulphonamido means —NHS(O)₂-alkyl, such as NHSO₂—CH₃,NHSO₂—C₂H₅, n-propylsulphon-amido, NHSO₂—CH(CH₃)₂, n-butylsulphonamido,1-methylpropylsulphonamido, 2-methylpropyl-sulphonamido, NHSO₂—C(CH₃)₃.Methylsulphonamido is preferred.

[0070] Alkylsulphone-N-alkylamido means —N(alkyl)S(O)₂-alkyl, where thenitrogen-bonded and the sulphur-bonded alkyl radicals can be identicalor different, e.g. N(CH₃)SO₂—CH₃.

[0071] Carbonyl, CHO, —COOH, —COCOOH, —SO₃H means>C═O, formyl, carboxy,carboxycarbonyl or sulpho.

[0072] “Aryl” is preferably naphthyl and in particular phenyl.

[0073] The term “halogen” includes a fluorine, chlorine, bromine oriodine atom and in particular a fluorine, chlorine or bromine atom. As arule, fluorine and chlorine atoms are preferred, if appropriate alsobromine atoms.

[0074] The “heterocyclic radical” is in particular a 5- or 6-memberedheterocyclic radical which can be aromatic or non-aromatic, mono- orbicyclic, and/or benzo-fused. The aromatic radicals includenitrogen-containing heterocyclic radicals, such as pyrrolyl, imidazolyl,pyrazolyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, especiallypyridyl, pyrimidyl and isoquinolinyl. The aromatic radicals also includethose heterocyclic radicals which contain an oxygen atom or a sulphuratom, such as thienyl, benzothienyl, furanyl and especiallybenzofuranyl. Also included here are heterocyclic radicals which containtwo or more different heteroatoms, such as thiazolyl, isothiazolyl,thiadiazolyl, isoxazolyl and oxazolyl. Preferred aromatic heterocyclicradicals are thienyl, pyridyl and thiazolyl. The non-aromatic radicalsinclude nitrogen-containing heterocyclic radicals, such as piperidinyland piperazinyl. These also include heterocyclic radicals which containtwo or more different heteroatoms, such as morpholinyl.

[0075] Substituted radicals, in particular alkyl, cycloalkyl, aryl andheteroaryl, are preferably mono-, di- or trisubstituted.

[0076] For substitution with halogen, it moreover applies that poly- andin particular perhalogenated, especially poly- and in particularperfluorinated, radicals should also be covered. Preferred radicals ofthis type are poly- and in particular perhalogenated aliphatic radicalsin which 2 or more or in particular all C-bonded hydrogen atoms arereplaced by a halogen atom and in particular a fluorine atom.Especially, mention may be made here of poly- and in particularperhalogenated alkyl, such as trifluoromethyl, 2,2,2-trifluoroethyl,perfluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl,perfluoropropyl, 1,1,1-trifluoroisopropyl,1,1,1,3,3,3-hexafluoroisopropyl, perfluoroisopropyl,4,4,4-trifluorobutyl, 3,3,4,4,4-pentafluorobutyl,2,2,3,3,4,4,4-heptafluorobutyl, perfluorobutyl, perfluoroisobutyl,perfluoro-sec-butyl and perfluoro-t-butyl and the corresponding poly-and in particular perchlorinated radicals.

[0077] The [α]-fused ring can be 6- or especially 5-membered,heterocyclic or especially alicyclic, and if alicyclic, then unsaturatedor especially saturated, and/or consequently substituted orunsubstituted.

[0078] The [α]-fused pyrrole compounds of the formula 1 according to theinvention in particular include those in which X is CR8R9 and A is abond between X and the atom carrying the radicals R6 and R7(pyrrolizines); X is CR8R9 and A is CR1OR11 (indolizines); X is NR12 andA is a bond between X and the atom carrying the radicals R6 and R7(pyrrolo[1,2-a]imidazoles); X is S and A is a bond between X and theatom carrying the radicals R6 and R7 (pyrrolo[2,1-b]thiazoles); X is Sand A is CR10R11 (pyrrolo[2,1-b] 1,3-thiazines); X is 0 and A is CR10R11(pyrrolo[2,1-b]1,3-oxazines); X is O and A is a bond between X and theatom carrying the radicals R6 and R7 (pyrrolo[2,1-b]oxazoles), where theradicals not mentioned can have the meanings indicated above.

[0079] If the [α]-fused ring is a 5-membered unsaturated radical, R4 andR6 are especially a bond, such as in pyrrolizine,pyrrolo[2,1-b]imidazole and pyrrolo[2,1-b]thiazole. If the [α]-fusedring is a 6-membered unsaturated radical, R4 and R6, such as inpyrrolo[2,1-b] 1,3-thiazine, pyrrolo[2,1-b] 1,3-oxazine or5,6-dihydroindolizine, and optionally also R8 and R10 are a bond, suchas in indolizine.

[0080] Without being bonded to a specific [α]-fused ring, according to aparticular embodiment of the present invention R4-R11, which can beidentical or different, are hydrogen or alkyl. According to anotherparticular embodiment, at least one of the radicals R4, R5, R6 and R7 ishydroxyalkyl, in particular hydroxymethyl, and the other radicals R4,R5, R6 and R7 independently of one another are H or alkyl, R4 preferablybeing hydroxyalkyl, in particular hydroxymethyl, R5 being H or alkyl andR6 and R7 independently of one another being H or alkyl. According to afurther particular embodiment, one of the radicals R8 and R9 is H,alkyl, hydroxyalkyl or alkoxyalkyl and the other is hydroxyl, alkoxy,carboxyl or acyloxy, or R8 and R9, together with the carbon atom towhich they are bonded, are a carbonyl group.

[0081] 6,7-Dihydro-5H-pyrrolizines are preferred, i.e. compounds of theformula 1 in which X is CR8R9, A is a bond between X and the atomcarrying the radicals R6 and R7 and R4, R5, R6, R7, R8, R9, which can beidentical or different, have the abovementioned meanings and arepreferably hydrogen or alkyl. In particular, mention may be made of6,7-dihydro-5H-pyrrolizines in which R4 to R9 are all hydrogen or atleast one of the radicals R4 to R9, for example R6 and/or R8 is alkyl,in particular methyl.

[0082] According to the invention, one of the radicals R1, R2, R3 is4-substituted phenyl (para-substituted phenyl), the substituent beingselected from certain sulphur-containing groups, namely from alkylthio,alkylsulphinyl, alkylsulphonyl, sulphamoyl, N-alkylsulphamoyl,N,N-dialkylsulphamoyl, alkylsulphonamido and alkylsulphone-N-alkylamido.Preferred substituents are alkylthio, alkylsulphinyl, alkylsulphonyl,sulphamoyl and alkylsulphonamido, in particular methylthio,methylsulphinyl, methylsulphonyl, sulphamoyl and methylsulphonamido,very particularly methylsulphonyl and sulphamoyl.

[0083] A—more advantageously lipophilic—second of the radicals R1, R2,R3 can be linear or branched, alicyclic or heterocyclic, non-aromatic oraromatic. On the one hand, aryl radicals, in particular phenyl radicals,on the other hand aliphatic and cycloaliphatic, in particular alkyl,cycloalkyl and cycloalkylalkyl radicals, are preferred. These radicalscan be substituted according to the above details. Substitution isadvantageous in particular for the first case, i.e. of arylsubstitution. Accordingly, the second of the radicals R1, R2, R3 is inparticular phenyl monosubstituted in the para or meta position, inparticular 4-substituted phenyl. Optionally present substituents arepreferably selected from alkyl groups, in particular methyl, andespecially electronegative groups, such as halogen atoms, in particularfluorine, and haloalkyl groups, in particular trifluoromethyl.

[0084] If the second of the radicals R1, R2, R3 is an alkyl radical, onthe one hand alkyl radicals having a relatively large number of carbonatoms, in particular the abovementioned C₄₋₆-alkyl radicals, and ofthese advantageously the branched and in particular the singly branched,and on the other hand alkyl radicals having a relatively low number ofcarbon atoms, especially methyl, are preferred.

[0085] If the second of the radicals R1, R2, R3 is a cycloalkyl radical,cyclohexyl is particularly advantageous.

[0086] If the second of the radicals R1, R2, R3 is a cycloalkylalkylradical, cycloalkylmethyl radicals are preferred, cyclopropylmethylbeing advantageous.

[0087] According to a preferred embodiment, the second of the radicalsR1, R2, R3 is a fluoroaliphatic, in particular a poly- or in particularperfluorinated aliphatic radical. In particular, mention may be madehere of poly- and perfluorinated alkyl radicals, i.e. especially thepreviously described alkyl radicals, in which 2 or more and inparticular all H atoms are replaced by fluorine atoms. This analogouslyapplies to cycloalkyl and cycloalkylalkyl radicals.

[0088] According to a particular embodiment of the present invention, athird of the radicals R1, R2, R3 is hydrogen, alkyl, haloalkyl,hydroxyalkyl, halogen, cyano, alkylsulphonyl, sulphamoyl or B—Y, inwhich B is alkylene or alkenylene, each of which can optionally besubstituted by hydroxyl or alkoxy, and Y is hydroxyl; in the context ofthis embodiment hydrogen, alkyl, haloalkyl, in particular CF₃ orhalogen, are preferred. If the third of the radicals is B—Y, B ispreferably alkylene which is optionally substituted by hydroxyl.

[0089] If the third radical is an alkyl radical, the relatively shortradicals are preferred here, where mention may in particular be made ofmethyl. Preferred alkoxycarbonyl radicals are methoxy- andethoxycarbonyl. Of the halogen atoms, chlorine and optionally bromineare preferred in this case.

[0090] A second and a third of the radicals R1, R2, R3, if they arevicinal to one another, together with the C atoms to which they arebonded, can also form a cycloaliphatic radical. If R2 and R3 areinvolved, this ring taken per se is an unsaturated ring, for example acyclopentenyl or cyclohexenyl ring, as is illustrated in the presentExample 32. If R1 and R2 are involved, the ring has two exocyclic doublebonds.

[0091] Preferably, the first and the second of the radicals R1, R2, R3are vicinal to one another, i.e. R1 and R2 or R2 and R3 are involved.This leads to advantages, in particular for the [0]-fused pyrrolecompounds according to the invention having bisaryl substitution.

[0092] In principle, the positions of the groups designated as first,second and third radicals are variable. It has proved advantageous ifthe first of the radicals R1, R2, R3 is in the position of R1 or R3. Ithas also proved advantageous if the second of the radicals R1, R2, R3 isin the position of R2.

[0093] Compounds in which R3 is CHO, —COOH, —COCOOH, —COOalkyl,—COOAlkphenyl, —COCOOalkyl or B—Y, in which B is alkylene or alkenylene,each of which can optionally be substituted by hydroxyl or alkoxy, and Yis —COOH, —COO-alkyl or —CHO, can be used as synthesis intermediates. Inthe context of this particular embodiment, preferred radicals B—Y are2-acetic acid and 3-propionic acid radicals.

[0094] The compounds according to the invention can be prepared in thefollowing way (in the schemes the radicals indicated have the previouslymentioned meanings, if not stated otherwise; details in brackets serveas illustrative examples). In the reaction schemes, acyl has themeanings indicated above. R is an alkyl radical if not stated otherwise.

[0095] The synthesis of sulphoxides and sulphones can be carried out viathe reduction of sulphonyl chlorides using base metals, such as iron andzinc, in acidic, aqueous systems to give suitable thiols, which are thenfirst alkylated to give thioethers and then oxidized stepwise usingperoxides.

[0096] A further possibility for the synthesis of sulphones proceeds viareduction of sulphonyl chlorides with base metals, such as iron andzinc, in neutral, buffered, aqueous systems, or using sulphites, to givesulphinates, which are then alkylated to alkylsulphinates and finallythermally rearranged to give the sulphones.

[0097] For example,6-(4-fluorophenyl)-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, whichcan be prepared from 2-benzylpyrroline and2-bromo-1-(4-fluorophenyl)ethanone according to the process described byLaufer et al. (J. Med. Chem. 1994, 37, 1894-1897), can be sulphonated inchlorosulphonic acid and converted to the sulphonyl chloride by means ofa suitable chlorinating agent, such as phosphorus pentachloride, butalso by means of excess chlorosulphonic acid, preferably in the presenceof heat. The sulphonyl chloride is then reduced in an aqueous solutionof sodium sulphite and a suitable base, e.g. sodium hydrogencarbonate atelevated temperature, e.g. 70° C. The anion of the sulphinic acidformed, which is in solution, is alkylated in, for example, anethanolic/aqueous system using an alkyl iodide and the alkyl sulphiniteprimarily formed is converted into the desired alkylsulphone by heating(e.g. 100° C.) for a number of hours (Reaction 1).

[0098] If necessary, a protective group is first introduced for theextremely reactive position 5 of the starting compound, e.g.6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine. Suitableprotective groups for reactive positions on pyrroles are carboxylic acidester groups, which can be prepared almost quantitatively via thereaction of these pyrroles, for example, with phosgene, diphosgene ortriphosgene and the subsequent alcoholysis of the carbonyl chloridesformed as intermediates. After introduction of the desired group hastaken place, the esters are hydrolysed and the pyrrolecarboxylic acidsisolated are thermally decarboxylated to the pyrroles.

[0099] Advantageously, the aromatics carrying the necessary sulphurfunctions can be introduced by means of suitable precursors even duringthe synthesis of the pyrrolizine structure, as a result of whichshortening of the synthesis sequence results. For example, the4-methylsulphanylbenzyl-2-pyrroline (7) necessary for the synthesis ofthe compound from Example 6 according to the technique outlined isaccessible via the Grignard reaction of 4-methylsulphanylbenzyl bromidewith magnesium and subsequent addition to 4-chlorobutyronitrile(Reaction 2).

[0100] Preferably, the preparation of the intermediate 7 is carried outvia the condensation of a 4-alkyl-sulphonylphenylacetic acid ester withN-vinyl-2-pyrrolidone in the presence of strong bases, e.g. NaH, Ktert-butoxide, etc. and subsequent hydrolytic cleavage anddecarboxylation of the 1-vinyl-3-acyl-2-pyrrolidone formed in high yieldas an intermediate (Reaction 3). For example, the reaction of theintermediate 7 with 2-bromo-1-(4-fluorophenyl)ethanone yields thepyrrolizine shown below (Example 6).

[0101] The necessary starting compounds 4-alkylmercaptophenylacetic acidesters, here methyl 4-methyl-mercaptophenylacetate, can be convenientlyprepared starting from thioanisole via Friedel-Crafts acylation withacetyl chloride and Willgerodt-Kindler rearrangement with subsequenthydrolysis and ester formation. The 4-alkylsulphonylphenylacetic acidesters can be obtained in good yields from the4-allkylmereaptophenylacetic acid esters by peracid oxidation, e.g.using m-chloroperbenzoic acid or H₂O₂ in glacial acetic acid, and can becondensed analogously to the sulphonyl compound to give a pyrroline 9and cyclized to the pyrrolizine of Example 7 (Reaction 4).

[0102] Diarypyrrolizine compounds according to the invention of the6,7-(or 1,2-) diaryl series, in which the sulphur function is positionedin the para position on the aromatic to position 6 (or position 2) ofthe pyrrolizine can also be prepared from the corresponding phenacylbromides which carry these sulphur functions in the case of thesulphanyl, sulphoxide, and of the sulphonyl and also the sulphamoylcompounds (Reaction 4b).

[0103] Thus, for example, the reaction of2-bromo-1-(4-methylsulphanylphenyl)-1-ethanone with 2-benzyl-1-pyrrolineyields the compound of Example 1, with 2-(4-fluorobenzyl)-1-pyrrolinethat of Example 4, the reaction of 2-bromo-1-(4-methylsulphinylphenyl)-1thanone with 2-benzyl-1-pyrroline the compound of Example 2, thereaction of 2-bromo-1-(4-methylsulphonylphenyl)-1-ethanone with2-benzyl-1-pyrroline that of Example 3, with2-(4-fluorobenzyl)-1-pyrroline the compound of Example 5.

[0104] Acyl side chains can also be introduced in position 5 of thepyrrolizine in the said 6,7-(or 1,2) diarylpyrrolizine compounds byacylation in position 5 (or 3) and these can be converted by suitablereduction methods (HI reduction, NaCNBH₃ reduction, Vitride reductionetc.) into alkyl side chains.

[0105] 5,6-(or 2,3) diarylpyrrolizine compounds and 6,7-(or 2,3)diarylindolizine compounds according to the invention can be prepared inthe manner of a 1,3-dipolar cycloaddition from corresponding münchnoneor sydnone precursor compounds and suitable dienophiles ordipolarophiles. In this case, a sulphur function can be introduced onthe one hand via the münchnone/sydnone component, on the other hand viathe dipolarophile component. Dipolarophiles used are dehydrocinnamicacids or other acetylene carboxylic acids, 2-halo-substituted cinnamicacids or 2-haloacrylates and nitrostyrenes. In the pyrrolizine series,N-acyl derivatives of proline (pyrrolidine-2-carboxylic acid) and in theindolizine series N-acyl derivatives of the homologouspiperidine-2-carboxylic acid are employed for sydnone formation.

[0106] For example, the cycloaddition of ethyl2-bromo-3-(4-methylsulphanylphenyl)propenoate (10) to the munchnone ofN-(4-fluorobenzoyl)proline (11, Reaction 5) produced in situ leads tothe ethyl ester of the pyrrolizinecarboxylic acid of Example 11, that ofethyl 2-bromo-3-(4-methylsulphonylphenyl)-propenoate (12) to the esterfrom Example 12, and the cycloaddition of a2-(4-methylsulphonyl-phenyl)-1-nitroethene (13) to the same münchnoneleads to the pyrrolizine compound from Example 13A.

[0107] By the use of, for example, methyl dehydrocinnamate (14),1-nitrostyrene or N-benzoylproline (15), unsubstituted 5,6-(or 2,3)diarylpyrrolizine compounds (Reaction 6) are first obtained into which asulphur function can subsequently be introduced into the para ringposition, for example, by chlorosulphonation.

[0108] This is carried out in analogy to the 6-aryl and 6,7-diarylcompounds according to the techniques mentioned above (see aboveReaction 1, Example 7): the reaction with chlorosulphonic acid in excessleads to the sulphonyl chlorides, which on the one hand can be convertedinto the sulphones by Na₂SO₃ reduction and alkylation with subsequentrearrangement (Reaction 7) and on the other hand can be converted intothe sulphonamides according to the invention in aqueous and non-aqueoussolutions of ammonia. For example, the reaction of methyl3-(4-fluorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizin-1-ylcarboxylatewith chlorosulphonic acid in excess, both in the cold and in thepresence of heat, leads with simultaneous loss of the carboxylic acidester function to4-[3-(4-fluoro-phenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonylchloride, which can then be converted into the sulphonamide of Example10 using ammonia.

[0109] A suitable alternative for access to 5,6-diaryl-substitutedpyrrolizines is especially offered by arylation according to Suzuli ifthe sulphur-containing aromatic is introduced in position 5.

[0110] For example, the reaction of a6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine, which wasobtained from 2-ethyl-1-pyrroline and 2-bromo-I4-fluorophenyl)-1-ethanone, with N-bromo-succinimide in THF at lowtemperatures (-70° C. to 25° C.) yields a5-bromo-6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine, which inthe presence of tetrakistriphenylphosphinepalladium(0) can be condensedin aqueous/alkaline (e.g. Na₂CO₃/CH₂Cl₂) medium with4-methyl-sulphanylphenylboronic acid according to Suzuki to give themethylsulphanyl compound from Example 9 (Reaction 8).

[0111] A suitable starting point for the6-alkyl-7-(4-sulphamoylphenyl)-substituted pyrrolizines is also7-phenyl-2,3-dihydropyrrolizine, which can be halogenated in position 5by NBS in THF or can be acylated in position 5 with reaction withacylating compounds such as acid chlorides and acid anhydrides (Reaction9).

[0112] Subsequently, after prior modification of this introduced acylfunction (cf. Reaction 9, 20, 21, reduction, condensation etc.), theremaining free pyrrole position (position 6) of the pyrrolizinestructure can be acylated again (Reaction 10). As a rule, beforeintroduction of the sulphochloride function, the acyl group is convertedinto an alkyl group. The Wolff-Kishner or Huang-Minlon reaction issuitable for this conversion, or the reaction with sodiumcyanoborohydride in the presence of zinc iodide. On the one hand, thesulphochlorides obtained are converted by ammonia into the sulphonamidesor, by reaction with sodium sulphite and methyl iodide, into thesulphones (see above Reaction 1).

[0113] As a starting point for the synthesis of cycloaliphaticallysubstituted pyrrolizines, e.g. of the 6-cyclohexyl derivatives, theacylated cycloaliphatics (e.g. cyclohexyl methyl ketone) can be used.Their bromination also leads to the desired bromoacetyl compounds. Thereaction of the 1-acetyl-1-ethoxycarbonylcycloalkyl, e.g. of1-acetyl-1-ethoxycarbonylcyclohexane, with bromine to give1-bromoacetyl-1-ethoxycarbonylcyclohexane, which also cyclizes smoothlyto give a pyrrolizine with pyrrolines, is more advantageous. Comparablyto l-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl acetic acid in Reaction 9(preparation of compound 20), the 6-ylacetic acid is also unstable anddecarboxylates at elevated temperature (Reaction 11, 24-COOH).

[0114] In this case, the ethoxycarbonyl group functions as a protectivegroup for the branching position in the 5 cycloaliphatic. Finally, thesulphochlorides are also obtained here using chlorosulphonic acid, andon the one hand are converted by ammonia into the sulphonamides (cf.Example 14) or into the sulphones by reaction with sodium sulphite andmethyl iodide (Reaction 12).

[0115] The intermediately obtained pyrrolizines, as well as thepyrrolizines carrying sulphur functions, can be converted further indifferent ways, for example further functional groups can be introducedinto the activated positions of the pyrrolizine nucleus, as is carriedout in WO 95/23970 and WO 95/23971. The α-positions of the aliphaticfused ring adjacent to the pyrrole nucleus (position 1, or 7) can befunctionalized by suitable methods: free-radical bromination withN-bromosuccinimide in aprotic solvents yields 1-bromo (or 7-bromo)derivatives, and in aqueous systems and in an excess of the reagent the1-oxo derivatives of the pyrrolizines.

[0116] When using 1 molar equivalent of N-bromosuccinimide, the compoundof the formula 25 brominated in the 1-position is obtained (Reaction13). This in turn can then be reacted with acylates, for example sodiumacetate or alkoxides, such as sodium methoxide or sodium ethoxide, togive the corresponding compounds of the formulae 26 and 27 (Reaction13). The reactions are carried out in a known manner, the reaction withthe acylates takes place in an inert solvent, for exampledimethylformamide (DMF), at elevated temperature, e.g. 70 to 90° C. Thereaction of the compounds of the formula 25 with alkoxides isexpediently carried out in the corresponding alcohol. Alternatively, thecompounds of the formula 25 (Reaction 13), if desired without beingisolated from the reaction mixture, can be reacted directly with analcohol to give the compounds of the formula 27.

[0117] Alternatively, a compound of the formula R can be reacted withone molar equivalent of NBS in a chlorinated solvent in the presence ofwater to give a compound of the formula 28. Using a further molarequivalent of NBS, a compound of the formula 29 is then obtained.

[0118] The introduction of polar groups on the hydrocarbon skeleton ofthe fused ring, i.e. in the position of the substituents R4-R11, such ashydroxyl groups (Reaction 14, 30), amino groups (Reaction 14, 31lZ=NR₂), carbonyl (Reaction 14, 32) and carboxyl groups (Reaction 14, 33)presupposes a modified synthesis strategy. Such functional groups canonly be indirectly introduced subsequently on the hydrocarbon skeletonof the fused ring. The preparation is carried out by means of suitableprecursors which already contain these functional groups, protected byso-called protective groups (=Pg) or can subsequently be converted intothe desired group from a suitable precursor group (e.g. 30).

[0119] Reaction 14 shows an example of how, using the methodologydescribed in EP 0397175, starting here from trishydroxymethylenederivatives (R4—R6═H, R8═R9═H, R7═CH₂OH) by selective introduction of aprotective group for one of the 3 hydroxymethylene groups, compounds ofthe structure 30, 31, 32 and 33 can be obtained which contain thecorresponding substitution pattern with functional groups. Thesecompounds (30, 31, 32 and 33) occur in the form of two optical antipodeswhich, if required, are separated by use of chromatographic techniquesor are separated using customary purification methods at the stage ofdiastereomeric synthesis intermediates (acetals or ketals where R═H,R′=alkyl, aryl etc, or R═R′=alkyl, aryl etc.). after their preparationand which yield the pure enantiomers of the precursors after recleavage.

[0120] In vitro, the compounds according to the invention show a markedinhibition of the release of proinflammatory mediators of thearachidonic acid cascade and thus in vivo antipyretic, analgesic andanti-inflammatory action in inflammation models. The compounds accordingto the invention inhibit prostaglandin H synthase, the key enzyme ofprostaglandin synthesis. In this case, its isoform 2 shows an increasedsensitivity to the compounds according to the invention, so that theseact as selective inhibitors of isoenzyme-2. The compounds thus allow amarkedly decreased side-effect profile, in particular on the kidney andGI tract, to be expected.

[0121] The compounds also exert a weak to medium inhibitory action on5-lipoxygenase, a further enzyme of arachidonic acid metabolism. Usingthe inhibitory action on 5-LO, similarly to dual inhibitors ofcyclooxygenase-1/2 (COX-1/COX-2) and of 5-lipoxygenase (5-LOX), thedisadvantageous effects of a pure COX-1 inhibition on bronchi (asthma)and GI tract (lesions) can be compensated.

[0122] The compounds according to the invention are thus suitable forthe treatment of disorders in which increased release rates of theeicosanoid mediators are responsible for the formation or theprogressive course of these disorders. In particular, the compoundsaccording to the invention, can be used for the treatment of disordersof the rheumatic type and for the prevention of allergically induceddisorders. The compounds according to the invention are thus efficaciousanti-inflammatories, analgesics, antipyretics, antiallergics andbroncholytics or have antibronchoconstrictor activity and can thereforebe used for thrombosis prophylaxis and for the prophylaxis ofanaphylactic and septic shock as well as for the treatment ofdermatological disorders, such as psoriasis, urticaria, acute andchronic exanthema, of allergic and non-allergic genesis.

[0123] The compounds according to the invention have increased chemicalstability, parenteral administrability, enteral bioavailability andshort half-lives.

[0124] The compounds according to the invention can either beadministered as individual therapeutic active compounds or as mixtureswith other therapeutic active compounds: they can be administered assuch, but in general they are administered in the form of pharmaceuticalcompositions, i.e. as mixtures of the active compounds withpharmaceutically acceptable excipients, in particular vehicles ordiluents and/or additives. The compounds or compositions can beadministered enterally, e.g. orally or rectally, or parenterally, e.g.subcutaneously, intravenously or intramuscularly, but they arepreferably given in oral dose forms.

[0125] The nature of the pharmaceutical composition and of thepharmaceutical carrier or diluent depends on the desired manner ofadministration. Oral compositions can be present, for example, astablets or capsules and can contain customary excipients, such asbinding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth orpolyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine), lubricants (e.g. magnesiumstearate, talc, polyethylene glycol or silica), disintegrating agents(e.g. starch) or wetting agents (e.g. sodium laurylsulphate). Oralliquid preparations can be present in the form of aqueous or oilysuspensions, solutions, emulsions, syrups, elixirs or sprays etc. or canbe present as dry powders for reconstitution with water or anothersuitable carrier. Liquid preparations of this type can contain customaryadditives, for example suspending agents, flavourings, diluents oremulsifiers. For parenteral administration, solutions or suspensionswith customary pharmaceutical carriers can be employed.

[0126] The use of compounds according to the invention in the course oftreatment comprises a process. In this case, an efficacious amount ofone or more compounds, as a rule formulated corresponding topharmaceutical and veterinary practice, is administered to theindividual to be treated, preferably a mammal, in particular a human,agricultural animal or pet. Whether such a treatment is indicated and inwhich form it has to be carried out, depends on the individual case andis subject to medical assessment (diagnosis) which includes presentsigns, symptoms and/or dysfunctions, risks of developing specific signs,symptoms and/or dysfunctions, and further factors.

[0127] As a rule, the treatment is carried out by administration one ormore times daily, if appropriate together or alternately with otheractive compounds or active compound-containing preparations, so that adaily dose of approximately 0.1 mg to approximately 1000 mg and inparticular 0.5 mg to approximately 100 mg per kg of body weight isadministered to an individual to be treated.

[0128] The following examples explain the invention without restrictingit.

[0129] FIGS. 1 to 9 show spectroscopic data of the compounds preparedaccording to Examples 1 to 36;

[0130]FIGS. 10 and 11 show biological activity data of some compoundsaccording to the invention and of known compounds for comparison.

SYNTHESIS

[0131] In general, the abbreviations have the following meanings Mp:melting point Bp: boiling point dec: decomposition TLC: thin-layerchromatography CC: column chromatography GC: gas chromatography Y: yieldTY: total yield abs. absolute In the context of NMR, the abbreviationshave the following meanings arom: aromatic; quin: quintuplet; br: broad;t: triplet; m: multiplet; s: singlet; q: quadruplet; d: doublet

[0132] The melting points were determined on a Mettler FP 51 or on aBtichi Melting Point B 545: heating rate 2° C./min, average value (40%threshold) of 3 measurements with a regular melting course (meltingcourse diagram), calibration against vanillin (83.0° C.), phenacetin(136.0° C.) and caffeine (237° C.).

[0133] The IR spectra were recorded on a Shimadzu IR 470; or FT-IRNicolet Impact 410, on the latter processed using Omnic (Version 2.1).For this, the substance was compressed in KBr tablets or measured as afilm between NaCl plates in transmitted light.

[0134] The NMR spectra were recorded on a Bruker AC 200 (1H: 200 MHz,13C: 50.3 MHz). For this, 20-50 mg of substance, in about 0.5-1.0 ml ofa deuterated solvent which contained 0.1% of tetramethylsilane as aninternal standard_were dissolved to give a clear solution. The solutionwas transferred to a 0.5 cm sample tube in the sample space. For ¹H-NMRspectra, as a rule 32 FIDs were summed under D-lock for ¹H-NMR spectraand converted into frequency spectra by the FT process; for therecording of ¹³C-NMR spectra between 500 and 10,000 FIDs were collected.

[0135] UV spectra Were recorded on a UV Perkin-Elmer 550 SE UVNISspectroscope. Measurement was carried out in 1 cm quartz cuvettes in asuitable solvent.

[0136] Mass spectra were recorded on a GC-MS system HP-MSD (HP 6890GC-HP 5973 MSD); after GC separation in a high vacuum (10⁻⁶ Torr)excitation was carried out by EI, at an electron energy of 70 eV.

[0137] The determination of volatile and thermostable compounds wascarried out by means of GC on GC-MSD. Separation was carried out, if noother details are given, on an HP-5MS column (30 m, 0.25 mm, 5%phenylmethylsilicone, 0.25 μm) using helium at a constant flow of 1.2 mland a split ratio of 50:1 according to the area method of TIC.

[0138] The determination of poorly volatile and thermolabile compoundswas carried out by means of HPLC on a Merck-Hitachi HPLC (L4000detector, L6200A intelligent pump, D 2500 chromato-integrator) accordingto the area method; UV absorption measured at the absorption maximum orat 256 nm. The column (if not stated otherwise LiChroCART 125-4;LiChrosphere 100 RP-18; 5 μm; from Merck, Darmstadt) was thermostatedusing a WO Electronics BFO-04 SV column oven (30° C.). As a ruleseparation was carried out using a gradient of a ternary mixture ofmethanol, acetonitrile and a 5 mmol NaH₂PO₄ buffer which is maintainedat a pH of 3.5 using H₃PO₄, using a flow rate of 1 ml/min afterinjection of 20 μl of a solution of 30-40 mg of the substance to beinvestigated in 100 ml of MeOH.

EXAMPLE 1

[0139] 2-(4-Methylmercaptophenyl)-1-phenyl-6.7-dihydro-5H-pfrrolizine

[0140] a) 3-Phenylacetyl-1-vinylpyrrolidin-2-one

[0141] (according to Ref. Haslego M. L., Maryanoff C. A., Scott L., andSorgi K. L., Heterocycles, 35, 643-647 (1993))

[0142] Sodium hydride (300 g, 60% strength in white oil, 7.5 mol) issuspended under nitrogen in abs. THF (tetrahydrofaran) (1400 ml) in a 3l three-necked flask and the suspension is heated for 30 min, duringwhich the initial evolution of hydrogen subsides. The mixture is allowedto cool to RT (room temperature) and a mixture of ethyl phenylacetate(457 g, 2.78 mol) and 1-vinyl-2-pyrrolidone (278 g, 2.5 mol) in THF abs.(400 ml) is then added dropwise via a dropping funnel.

[0143] The addition rate is chosen such that the evolution of hydrogencan be kept under control (3.5 h). After complete addition, reflux (66°C., IT (internal temperature)) is maintained for a further 3 h; themixture is cooled to RT and allowed to stand for 16 h. The excess ofsodium hydride is destroyed by cautious addition of a saturated (37%strength) ammonium chloride solution (2 l) to the starting solution. Theorganic phase is separated in a separating funnel, dried with Na₂SO₄ andthe filtrate is concentrated. The white oil depositing as an independentphase is decanted off. An oily residue of 569 g (99.4%) having a purityof 90% GC (gas chromatography) remains: 8-9% of ethyl phenylacetate. Thematerial obtained can be employed in the next step without furtherpurification.

[0144] IR (NaCl): 1/λ (cm⁻¹)=3307 (br), 3030 (CH), 2960, 2893 (CH), 1693(CO), 1633, 1454, 1427, 1389, 1279, 700;

[0145]¹H-NMR (CDCl₃): δ (ppm)=7.37-7.15 (m, 5H, arom), 7.09-6.97 (ABX,1H, N—CH═), 4.52-4.40 (ABX, 2H, ═CH₂), 4.19-4.00 (AB, 2H, PhCH₂CO),3.82-3.73 (m,1H, 3-H), 3.53-3.39 (m, 2H, 5-CH₂), 2.80-2.40 (m,1H, 4-H),2.20-1.90 (m, 1 H, 4-H);

[0146]¹³C-NMR (CDCl₃): δ (ppm)=203.0 (CO), 173.3 (CONR), 133.7(C-quart.), 129.7, 128.6, 126.9 (CH), 52.7 (C-3), 49.3 (CH₂), 40.3(CH₂), 22.4 (CH₂).

[0147] b) 2-Benzyl-1-pyrroline

[0148] (according to Ref. Haslego M. L., Maryanoff C. A., Scott L., andSorgi K. L., Heterocycles, 35, 643-647 (1993))

[0149] A 6 N HCl solution is prepared in a 5 l three-necked flask usingwater (1.3 l) and HCl (36%, 1.3 l, 15 mol), and this is then heated toreflux. The crude 3-phenylacetyl-1-vinylpyrrolidin-2-one (552 g, 2.5mol) in THF (1 l) is added dropwise to the hot acid via a droppingfunnel, and the volatile acetaldehyde immediately released is distilledfrom the mixture via a distillation bridge (time needed 2 h).

[0150] The mixture is kept under reflux for a further 16 h and, aftercooling in an ice bath, treated with toluene (0.7 l) at RT. The organicphase is separated in a separating funnel and the HCl phase is extractedwith diethyl ether (0.7 l). The extracts are discarded. The aqueousphase is rendered alkaline (pH 9-10) using sodium hydroxide solution(32%, 11, 10 mol) while cooling with crushed ice (0.4 kg). The oildepositing in the course of this is taken up in diethyl ether (0.7 l),and the separated aqueous phase is extracted again with diethyl ether(0.7 l). The combined ether solution is washed with water (1 l), driedover Na₂SO₄ sicc. (dried), and the filtrate is concentrated. 304 g (75%)of 2-benzyl-1-pyrroline of 90% purity (GC) are obtained.

[0151] Y: 75% =304 g (90%);

[0152] Mp: oily;

[0153] IR (NaCl): 1/λ (cm⁻¹)=3350 (br), 3028 (CH), 2958, 2868 (CH),1641, 1603, 1495, 1454, 1429, 704;

[0154]¹H-NMR (CDCl₃): δ (ppm)=7.35-7.19 (m, 5H, CH, arom), 3.88-3.78 (t,2H, 5-CH₂), 3.68 (br, 2H, PhCH₂), 2.44-2.34 (t, 2H, 3-CH₂), 1.91-1.75(quin, 2H, 4-CH₂);

[0155]¹³C-NMR (CDCl₃): δ (ppm)=176.8 (C-2), 136.8 (C-quart.), 128.9,128.5, 126.5 (CH), 60.7 (CH₂), 40.5 (CH₂), 36.4 (CH₂), 22.5 (CH₂).

[0156] c) 2-(4-Methylmercaptophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine

[0157] 2-Benzyl-1-pyrroline (2.0 g, 80% strength, 10 mmol), dissolved inMeOH (30 ml), is treated with a solution of2-bromo-1-(4-methylsulphanylphenyl)-1-ethanone (Example 2, 2.0 g, 8mmol) in CH₂Cl₂ (10 ml) and then with NaHCO₃ (1.5 g, 18 mmol). Themixture is stirred at RT until a TLC sample (Al₂O₃, hexane/ether 9:1)indicates the complete reaction of the bromoketone (Rf=0.75) and anadequate formation of product (Rf=0.5) (48 h). After addition of water(50 ml), the mixture is extracted with diethyl ether (3×30 ml) and thecombined extracts are dried over Na₂SO₄ sicc. and concentrated. Theresidue is purified by CC (Al₂O₃, hexane/ether 9:1). 0.62 g (25.2%) ofthe compound sought is isolated.

[0158] Mp: 112° C.

[0159] IR(NaCl): 1/λ (cm⁻¹))=3050, 1695, 1595, 1521, 1484, 1335, 1179,1003;

[0160]¹ ¹H-NMR (CDCl₃): δ (ppm)=7.25-7.10 (m, 9H, arom), 6.72 (s, 11H,CH), 3.98 (t, 2H, CH₂), 2.96 (t, 2H, CH₂), 2.52-2.48 (quin, 2H, CH₂),2.44 (s, 3H, SCH₃).

EXAMPLE 2

[0161] 2-(4-Methylsulphinylahenyl)-1-phenyl-6.7-dihydro-5H-pyrrolizine

[0162] a) 1-(4-Methylsulphanylphenyl)-1-ethanone

[0163] Acetyl chloride (8.2 g, 0.105 mol) is added to a suspension ofAlCl₃ (16 g, 0.12 mol) in dichloroethane (50 ml) cooled to 0° C.; themixture is stirred for 15 min and a solution of thioanisole (12.4 g, 0.1mol) in dichloroethane (20 ml) is then added dropwise; the temperatureis kept below 20° C. by cooling (30 min). The mixture is stirred for afurther 1 h and allowed to stand at RT overnight. The Lewis acid complexis decomposed by addition of ice water (100 ml) with cooling, theorganic phase is separated in a separating funnel, and the aqueous phaseis extracted a further 2 times with dichloroethane (100 ml). Thecombined extracts are dried over Na₂SO₄ sicc. and concentrated to ¼ ofthe starting volume. The red-brown residue (15.2 g) is washed withdiethyl ether (20 ml) and hexane (20 ml): 12 g of light red (brick-red)substance result.

[0164] Y: 72% (12 g) C₉H₁₀OS, MW=166.24;

[0165] IR (NaCl): 1/λ (cm⁻¹)=1664;

[0166]¹H-NMR (CDCl₃): δ (ppm)=7.89-7.85 (m, 2H, AA′, arom), 7.28-7.24(m, 2H, BB′, arom), 2.57 (s, 3H, COCH₃), 2.52 (s, 3H, SCH₃).

[0167] b) 2-Bromo-1-(4-methylsulphanylphenyl)-1-ethanone

[0168] A solution of bromine (4.8 g, 30 mmol) in CH₂Cl₂ (20 ml) is addeddropwise at room temperature in the course of one hour to a solution of1-(4-methylsulphanylphenyl)-1-ethanone (5 g, 30 mmol) in CH₂Cl₂ (10 ml).The mixture is stirred further for one hour until the disappearance ofthe starting material

[0169] (TLC checking SiO₂, CH₂Cl₂/hexane 1:1). After this, it is pouredonto water (30 ml), the aqueous phase is separated and the organic phaseis washed with NaHCO₃ soln (20 ml, 8% strength) until neutral, thendried (Na₂SO₄ sicc.) and concentrated.

[0170] Y: 95% (7.0 g), C₉H₉BrOS, MW=245.14;

[0171] Mp: 67-68° C. from hexane;

[0172] IR (NaCl): 1/λ (cm⁻¹)=3005, 2945, 1687, 1581, 1551, 1402, 1313,1281, 1202, 1189, 1091, 992, 969, 956, 816, 728, 660;

[0173]¹H-NMR (CDCl₃): δ (ppm)=8.20-8.05 (AA′BB′, 4H, arom), 4.46 (s, 2H,CH₂Br), 3.10 (s, 3H, SCH₃).

[0174] b′) 2-Chloro-1-(4-methylsulphanylphenyl)-1-ethanone

[0175] Chloroacetyl chloride (11.8 g, 0.105 mol) is added to asuspension of AlCl₃ (16 g, 0.12 mol) in dichloroethane (50 ml) cooled to0° C.; the mixture is stirred for 15 min and a solution of thioanisole(12.4 g, 0.1 mol) in dichloroethane (20 ml) is then added dropwise; thetemperature is kept below 20° C. by cooling (30 min). The mixture isstirred for a further 1 h and then decomposed by addition of ice water(100 ml) with cooling of the Lewis acid complex, the organic phase isseparated in a separating funnel and the aqueous phase is extracted afurther 2 times with CHCl₃ (100 ml). The combined extracts are driedover Na₂SO₄ sicc. and concentrated to ¼ of the starting volume. Thered-brown residue is treated with hexane (20 ml), and the crystallizingproduct is filtered off with suction and recrystallized from hexane: 4 g(20%) of salmon-coloured substance are obtained.

[0176] Mp: 76.5° C. from hexane; Y: 20% (4 g) C₉H₉ClOS, MW=200.69;

[0177] IR (NaCl): 1/λ (cm⁻¹)=1687, 1577, 1546, 1394, 1213, 1086, 817;

[0178]¹H—NNM (CDCl₃): δ (ppm)=7.89-7.44 (m, 2H, AA′, arom), 7.51-7.26(m, 2H, BB′, arom), 4.66 (s, 2H, COCH₂Cl), 2.53 (s, 3H, SCH₃).

[0179] c) 1-Bromo-2-(4-methylsulphinylphenyl)-2-ethanone

[0180] A solution of 2-bromo-1-(4-methylsulphanylphenyl)-1-ethanone (3.7g, 15 mmol) in CHCl₃ (50 ml) is maintained at a temperature of −5° C. Asolution of m-chloroperbenzoic acid (70%, 3.7 g, 15 mmol) in CHCl₃ (30ml) cooled to 0° C. is added dropwise while maintaining an IT of −5° C.to 0° C. After stirring for 1₂ hour in the cold, the depositedm-chlorobenzoic acid is filtered off. The filtrate is first washed withNaHCO₃ solution (8% strength, 50 ml) until acid-free and then rewashedwith water (50 ml). The CHCl₃ phase dried over Na₂SO₄ sicc. isconcentrated in vacuo. A yellowish residue (1.3 g) results.

[0181] Y: 95% (1.3 g) C₉H₉BrO₂S, MW=261.14;

[0182] IR (NaCl): 1/λ (cm⁻¹)=1763, 1706, 1569, 1396, 1290, 1202, 1149,1103, 997, 956, 826, 758;

[0183]¹H-NMR (CDCl₃): δ (ppm)=8.2-8.07 (AA′BB′, 4H, arom), 4.71 (s, 2H,CH₂Cl), 2.80 (s, 3H, SOCH₃).

[0184] d)2-(4-Methylsulphinylphenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine

[0185] 2-Benzyl-1-pyrroline (2.0 g, 80% strength, 10 mmol), dissolved inMeOH (30 ml), is treated with a solution of 4-methylsulphinylphenacylbromide (2.1 g, 8 mmol) in CH₂Cl₂ (10 ml) and then with NaHCO₃ (1.5 g,18 mmol) and the mixture is stirred at RT until a TLC sample (Al₂O₃,hexane/ether 9:1) indicates the complete reaction of the bromoketone (Rf0.75) and an adequate formation of product (Rf=0.2) (48 h). Afteraddition of water (50 ml), the mixture is extracted with diethyl ether(3×30 ml), and the combined extracts are dried over Na₂SO₄ sicc. andconcentrated. The residue is purified by CC (Al₂O₃, hexane/ether 1:1).0.3 g (12%) of the compound sought is isolated.

[0186] Y: 12% (0.3 g), C₂₀H₁₉NOS, MW=321.44

[0187] IR (NaCl): 1/λ (cm⁻¹)=2912, 1586, 1457, 1301, 1140, 1088, 959,829, 774;

[0188]¹H-NMR (CDCl₃): δ (ppm)=7.93-7.64 (4H, arom), 7.53-7.40 (4H,arom), 6.88 (s, 1H), 4.23 (t, CH₂), 3.16 (t, CH₂), 3.08 (s, CH₃), 2.65(m, CH₂).

EXAMPLE 3

[0189] 2-(4-Methylsulphonnlphenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine

[0190] a) 2-Bromo-1-(4-methylsulphonylnhenyl)-1-ethanone

[0191] (prepared according to J. Org. Chem. 35, 2106 (1970))

[0192] A solution of 1-bromo-2-(4-methylsulphanylphenyl)-2-ethanone(1.25 g, 5 mmol) in CHCl₃ (30 ml) is maintained at a temperature of −5°C. A solution of m-chloroperbenzoic acid (3.5 g, 10 mmol) in CHCl₃ (30ml) cooled to 0° C. is added dropwise while maintaining an IT of −5° C.to 0° C. After stirring in the cold for 3 hours, the depositedm-chlorobenzoic acid is filtered off. The filtrate is first washed withNaHCO₃ solution (8% strength, 50 ml) until acid-free and then rewashedwith water (50 ml). The CHCl₃ phase dried over Na₂SO₄ sicc. isconcentrated in vacuo until a reddish-brown solid substance deposits.The solid deposited from the cooled mother liquor (1.3 g) is collected.

[0193] Y: 95% (1.3 g) C₈H₈BrO₃S, MW=184.22;

[0194] Mp: 117.3° C.;

[0195] IR (NaCl): 1/λ (cm⁻¹)=3085, 2935, 1697, 1568, 1335, 1296, 1191,1145, 1085, 1006, 997, 882, 784, 653;

[0196]¹H-NMR (CDCl₃): δ (ppm)=8.20-8.05 (AA′BB′, 4H, arom), 4.46 (s, 2H,CH₂Br), 3.10 (s, 3H, SO₂CH₃).

[0197] b)2-(4-Methylsulphonylphenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine

[0198] 2-Benzyl-1-pyrroline (2.0 g, 80% strength, 10 mmol), dissolved inMeOH (30 ml), is treated with a solution of 4-methylsulphonylphenacylbromide (2.3 g, 8 mmol) in CH₂Cl₂ (10 ml) and then with NaHCO₃ (1.5 g,18 mmol) and the mixture is stirred at RT until a TLC sample (Al₂O₃,hexane/ether 9:1) indicates the complete reaction of the bromoketone(Rf=0.75) and an adequate formation of product (Rf=0.5) (48 h). Afteraddition of water (50 ml), the mixture is extracted with diethyl ether(3×30 ml), and the combined extracts are dried over Na₂SO₄ sicc. andconcentrated. The residue is purified by CC (Al₂O₃, hexane/ether 9:1).0.6 g (25%) of the compound sought is isolated.

[0199] Mp: 165, Y 25% (0.6 g), C₂₀H₁₉NO₂S, MW=337.44;

[0200] IR(NaCl): 1/λ (cm⁻¹)=3172, 1590, 1311, 1148, 951, 771, 546

[0201]¹H-NMR (CDCl₃): δ (ppm)=7.80-7.76 u. 7.43-7.38 (AA′BB′, 4H, arom),7.09-6.96 (m, 4H, arom), 4.23-4.12 (q, J=7.1 Hz, 2H), 4.03-3.96 (t,J=7.2 Hz, 2H), 3.27-3.19 (t, J=7.4 Hz, 2H), 3.05 (s, CH₃), 2.63-2.49(quin, J=7.2 Hz, 2H), 1.26-1.19 (t, J=7.0 Hz, CH₃).

EXAMPLE 4

[0202]2-(4-Methylmercaptophenyl)-1-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolizine

[0203] a) 2-(4-Fluorobenzyl)-1-pyrroline

[0204] 4-Fluorotoluene (5.5 g, 0.05 mol), N-bromosuccinimide (NBS, 8.9g, 0.05 mol) and azaisobutyronitrile (AIBN, 160 mg, 1 mmol) aredispersed in carbon tetrachloride (CCl₄, 40 ml); the mixture is stirredat 75° C. for 3-4 h. After cooling, the deposited succinimide isfiltered off. The residue is rewashed with CCl₄ (10 ml). Onconcentrating in vacuo, 8.5 g of 4-fluorobenzyl bromide (89%) areobtained from the combined CCl₄ phases as a yellow oil.

[0205] Magnesium turnings (for Grignard, 6.4 g, 0.266 mol) are coveredwith a layer of 20 ml of a solution of 4-fluorobenzyl bromide (50 g,0.265 mol) in abs. (absolute) diethyl ether (250 ml) in a 500 mlthree-necked flask and the mixture is briefly heated until the reactionstarts. The remaining volume of 4-fluorobenzyl bromide is added dropwisein the course of 30 min and at the same time the mixture is kept at atemperature of 40° C. for a further 2 h in an oil bath. A solution of4-chlorobutyronitrile (13.6 g, 0.132 mol) in diethyl ether (50 ml) isadded dropwise in the course of 30 min to the still warm, freshlyprepared Gringnard solution. The largest part of the ether (200 ml) isdistilled off over a bridge and replaced by abs. toluene (250 ml).Diethyl ether is driven off until a boiling temperature of 95° C. isachieved in the bottom. The mixture is stirred at this temperature for afurther 2 h and then allowed to stand at RT overnight. The organic phaseis transferred to a separating funnel and hydrolysed and extracted with10% strength HCl (3×100 ml each). The toluene phase is discarded, andthe HCl-acidic aqueous phase is again washed with toluene (100 ml) andthen maintained at pH 10 using conc. NaOH (32% strength). The pyrrolinebase depositing is taken up with diethyl ether (100 ml) in theseparating funnel. After separating the ether phase, the mixture isagain extracted with ether (2×50 ml), and the combined ether phases aredried over K₂CO₃ sicc. and concentrated. 8.8 g of2-(4-fluorobenzyl)-1-pyrroline (37.8% based on chloronitrile) areobtained.

[0206] Bp: 150-153° C., yellow-orange oil, C₁₁H₁₂FN, MW=177.22;

[0207] IR (NaCl): 1/λ (cm⁻¹)=2957, 2868, 1641, 1603, 1509, 1430, 1222,1157.5, 837, 825;

[0208]¹H-NMR (CDCl₃): δ (ppm)=7.26-6.94 (m, 4H, arom), 3.83 (t, 2H,CH₂), 3.64 (s 2H, CH₂), 2.39 (t, 2H, CH₂), 1.87 (quin 2H, CH₂).

[0209] b)1-(4-Fluorophenyl)-2-(4-methylsulphanylphentl)-6,7-dihydro-5H-pyrrolizine

[0210] 2-Bromo-1-(4-methylsulphanylphenyl)-1-ethanone (0.83 g, 3.4mmol), dissolved in diethyl ether (10 ml), is treated with a solution of2-(4-fluorobenzyl)-1-pyrroline (0.6 g, 3.3 mmol) in ethanol (10 ml) andNaHCO₃ (0.6 g, 7 mmol). The mixture is stirred in the dark at RT for 18h. The reaction is checked by TLC: SiO₂/hexane-ether 9:1. The mixture istreated with H₂O (10 ml), extracted 2 times with diethyl ether (100 ml)and the combined ether phase is then rewashed with water (30 ml). Theorganic phase dried over Na₂SO₄ Sicc. is concentrated in vacuo. Theresidue which remains is purified by CC on Al₂O₃/hexane/diethyl ether1:1. Fractions 1-3 afford 330 mg of orange-red oil.

[0211] Y: 33% (330 mg), C₂₀H₁₈FNS, MW=323.44;

[0212]¹H-NMR (CDCl₃): δ (ppm)=7.27-6.89 (2 AA′BB′, 8H, 2 arom), 6.74 (s,1H, CH), 4.04-3.97 (t, 2H, CH₂), 2.97-2.90 (tr, 2H, CH₂), 2.59-2.48 (m,2H, CH₂), 2.46 (s, 3H, SCH₃).

EXAMPLE 5

[0213]1-(4-Fluorphenyl)-2-(4-methylsulphonylphel)-6,7-dihydro-5H-pyrrolizine

[0214] 2-Bromo-1-(4-methylsulphonylphenyl)-1-ethanone (2.6 g, 9.5 mmol),dissolved in THF (30 ml) is treated with the solution of2-(4-fluorobenzyl)-1-pyrroline (1.77 g, 10 mmol) in methanol (50 ml) andNaHCO₃ (1.7 g, 20 mmol). The mixture is stirred in the dark at RT for 70h, water (30 ml) is added and it is stirred for a further 5 h. It isextracted 3 times with diethyl ether (100 ml), and the combined etherphase is then rewashed with water (50 ml) and concentrated in vacuoafter drying over Na₂SO₄ sicc. The residue which remains is purified byCC on Al₂O₃/ethyl acetate. Fractions 34 afford 1.9 g having a meltingpoint of 169.1° C.

[0215] Y: 56% (1.9 g), C₂₀H₁₈FNO₂S, MW=355.43;

[0216] IR (NaCl): 1/λ (cm⁻¹)=2924, 1592, 1528, 1502, 1404, 1307, 1215,1152, 1090, 948, 841, 766;

[0217]¹H-NMR (CDCl₃): δ (ppm)=7.78-7.74/7.39-7.34 (AA′BB′, 4H, arom),7.29-6.92 (m, 4H, arom), 6.85 (s, 1H, CH), 4.09-4.02 (t, 2H, CH₂), 3.05(s, 3H, CH₃), 2.97-2.90 (t, 2H, CH₂), 2.62-2.49 (quin, 2H, CH₂).

EXAMPLE 6

[0218]2-(4-Fluorophenyl)-1-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine

[0219] a) 2-(4-Methylsulphanylbenzyl)-1-pyrroline

[0220] Sodium hydride (23.9 g, 60% strength in white oil, 0.59 mol) issuspended in abs. THF (150 ml) under nitrogen, and the suspension isheated to reflux. A mixture of ethyl (4-methylsulphanylphenyl)acetate(38 g, 0.18 mol) and I-vinyl-2-pyrrolidone (20 g, 0.18 mol) in THF abs.(70 ml) is then allowed to run in dropwise via a dropping funnel. Theaddition rate is chosen such that the evolution of hydrogen can be keptunder control (1.5 h). After complete addition, the reflux (66° C., IT)is maintained for a further 4 h; the mixture is then cooled to RT. Theexcess of sodium hydride is destroyed by cautious addition of asaturated (37% strength) ammonium chloride solution (150 ml) to thecooled starting solution. The THF phase is separated in a separatingfunnel, and solid precipitated in the aqueous phase is brought intosolution by addition of water and extracted with THF (100 ml). The THFphase is dried with Na₂SO₄ sicc. and the filtrate is concentrated. Thedepositing white oil is decanted off. An oily residue of 57 g (115%)having a purity of 80% remains (GC: ethyl4-methylsulphanylphenylacetate, THF, paraffin) The material obtained isemployed in the next step without further purification.

[0221] 6N HCl (400 ml) is heated to reflux in a 1 l three-necked flaskhaving a water separator. The solution of the crude3-(4-methylsulphanylphenylacetyl)-1-vinylpyrrolidin-2-one (58 g, 80%strength, 170 mmol) in THF (200 ml) is added dropwise via a droppingfunnel to the hot acid, and the volatile acetaldehyde immediatelyreleased is distilled from the mixture together with THF via the waterseparator (time needed 2 h).

[0222] The mixture is refluxed for a further 6 h and treated with CHCl₃(200 ml) at RT after cooling in an ice bath. The organic phase isseparated in a separating funnel and discarded; the HCl phase isrendered alkaline (pH 11-12) using sodium hydroxide solution (32%, 400ml) while cooling with crushed ice (0.2 kg). The oil depositing in thecourse of this is taken up in CHCl₃ (100 ml) and the separated aqueousphase is extracted 2 times with CHCl₃ (200 ml). The combined CHCl₃solution is washed with water (1 l), dried over Na₂SO₄ sicc. and thefiltrate is concentrated. 22.3 g (64.3%) of2-(4-methylsulphanylbenzyl)-1-pyrroline of 80% purity (GC) are obtained.

[0223] Y: 64.3% =22.3 g (80%),

[0224] Mp: oily, C₁₂H₁₅NS, MW=205.32;

[0225] IR (NaCl): 1/λ (cm⁻¹)=3238, 2920, 2866, 1690, 1640, 1493, 1424,1092;

[0226]¹H-NMR (CDCl₃): δ (ppm)=7.23-7.12 (AA′BB′, 4H, arom), 3.9-3.75 (m,2H, CH₂), 3.63 (br, 2H, CH₂), 2.465 (s, 3H, SCH₃), 2.45-2.35 (m, 2H,CH₂), 1.90-1.79 (quin, 2H, CH₂).

[0227] b)2-(4-Fluorophenyl)-1-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine

[0228] 2-(4-Methylsulphanylbenzyl)-1-pyrroline (19.3 g, 80% strength,0.1 mol), dissolved in MeOH (100 ml), is treated with a suspension of2-bromo-1-(4-fluorophenyl)-1-ethanone (21.7 g, 0.1 mol) in MeOH (50 ml)and then treated with NaHCO₃ (8.4 g, 0.1 mol) and stirred at RT for 72 h(TLC sample (Al₂O₃, hexane/ether 9:1)).

[0229] The solid deposited from the MeOH phase is filtered off,dissolved in acetone, undissolved salts are filtered off and acetone isremoved in vacuo. The residue is digested with hot diisopropyl ether andcrystallized from this in the cold: 3 g of brown-coloured crystalsresult.

[0230] The MeOH filtrate solution is concentrated and digested withdiethyl ether. The crystalline brown bottom material (9 g) obtained isdiscarded.

[0231] The diethyl ether extracts are combined and concentrated. Theresidue (10 g), a red-brown viscous oil, is purified by CC onSiO₂/CHCl₃. 3 g (9.3%) of the compound sought are obtained.

[0232] Y: 9.3% (3 g); C₂₀H₁₈FNS, MW=323.44;

[0233] Mp: oily;

[0234] IR (NaCl): 1/λ (cm⁻¹)=3424, 2918, 1691, 1596, 1493, 1402, 1223,1156, 1090, 837;

[0235]¹H-NMR (CDCl₃): δ (ppm)=7.23-7.10 (m, 6H, arom), 7.0-6.88 (m, 2H,F-arom), 4.01 (t, 2H, CH₂), 2.96 (t, 2H, CH₂), 2.522 (quin, 2H, CH₂),2.460 (s, 3H, SCH₃);

[0236] GC-MS: m/e (rel. int.[%])=323 (M^(+), 100%), 308 ((M-CH₃ ^())⁺,10%).

EXAMPLE 7

[0237] Methyl4-[2-(4-fluoropheny)l-6.7-dihydro-5H-pyrrolizin-1-y]phenylsulphone(synonym2-(4-fluorophenyl)-1-(4-methanesulphonylhenyl)-6,7-dihydro-5H-pyrrolizine)

[0238] a) Methyl2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0239] A solution of6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (preparedaccording to Laufer et al., 1.11 g, 4 mmol) in CHCl₃ (20 ml) is cooledto 0° C. in an ice bath, treated with triethylamine (0.44 g, 4.4 mmol),and diphosgene (0.43 g, 2.2 mmol), dissolved in CHCl₃ (5 ml) is addeddropwise. After addition is complete, the mixture is stirred at RT for afurther 4 h in the cold. After addition of MeOH (4 ml), it isadditionally stirred at RT for 16 h. The reaction solution is washedwith water, and then with Na₂CO₃ solution (10%) until acid-free andfinally washed again with water. The separated CHCl₃ phase is driedusing Na₂SO₄ sicc. and concentrated. As a residue, 1.3 g (100%) ofmethyl2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate areobtained (GC. 93%). The substance is used in the next reaction stepwithout further purification.

[0240] Y: 100% =1.3 g (93%), C₂₁H₁₈FNO₂, MW=335.38.

[0241] Mp: 160.0° C.

[0242] IR (NaCl): 1/λ (cm⁻¹)=2997, 2955, 2900, 1701(ester), 1600, 1550,1525, 1469, 1401, 1313, 1217, 1121, 1095, 847, 783, 698;

[0243]¹H-NMR (CDCl₃): δ (ppm)=7.24-6.95 (m, 9H, arom.); 4.38 (t, 2H,CH₂, J=7.2 Hz); 3.64 (s, 3H, CH₃,); 3.02 (t, 3H, CH₂); 2.54 (quin, 2H,CH₂);

[0244] GC-MS: m/e (rel. int.[%])=335 (M^(+), 100%), 304 ((M-OCH₃^())⁺, 22%), 276 ((M-COOCH₃ ^()) ⁺, 22%), 248 (10%).

[0245] b)4-[2-(4-Fluorophenyl)-3-methoxycarbonyl-6,7-dihydro-5H1-pyrrolizin-1-yl]benzenesulphonylChloride

[0246] Methyl2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(1.3 g, 3.8 mmol) is dissolved in dried (CaCl₂ sicc.) CHCl₃ (10 ml)under nitrogen. Chlorosulphonic acid (2.66 g, 22.8 mmol) in CHCl₃ (5 ml)is then allowed to run in dropwise via a dropping funnel. After additionis complete, the mixture is stirred at RT for 16 h.

[0247] The starting solution is poured onto ice/water (80 ml) and thedeposited CHCl₃/oil phase is taken up in further CHCl₃ (20 ml). TheCHCl₃ phase is separated in a separating funnel, and the aqueous phaseis saturated with NaCl and again extracted with CHCl₃ (30 ml). Thecollected CHCl₃ phase is dried using Na₂SO₄ sicc., and the filtrate isconcentrated. The product depositing on concentration is filtered offwith suction. 1.7 g (106%) remain, which are employed in the next stepwithout further purification.

[0248] Y: 106% =1.7 g (85% gc), C₂₁H₁₇ClFNO₄S, MW=433.89;

[0249] IR (NaCl): 1/λ (cm⁻¹)=1693, 1587, 1525, 1371, 1225, 1177, 1094,837, 584, 561;

[0250]¹H-NMR (CDCl₃): δ (ppm)=7.83-7.78 (AA′, 2H, arom), 7.22-6.97 (m,6H, BB′+F-arom), 4.428 (t, 2H, J=7 Hz, CH₂), 3.657 (s, 3H, OCH₃), 3.082(t, 2H, J=7 Hz, CH₂), 2.609 (quin, 2H, J=7 Hz);

[0251] c) Methyl2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7dihydro-5H-pyrrolizine-3-carboxylate

[0252]4-[2-(4-Fluorophenyl)-3-methoxycarbonyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonylchloride (1.7 g, 3.8 mmol), suspended in water (10 ml), is treated withNa₂SO₃ (0.56 g, 4.4 mmol) and then with Na₂CO₃ (0.72 g, 6.8 mmol) andstirred at 70° C. for 2 h. The solution is treated with a solution ofCH₃I (0.88 g, 6.2 mmol) in ethanol (20 ml) and heated under reflux for 2h. After cooling, the ethanol is removed in vacuo, the residue istreated with water (25 ml) and the product from the reaction is taken upin ethyl acetate (2×30 ml). The ethyl acetate phase is washed with conc.NaCl solution and water, dried using Na₂SO₄ sicc. and the filtrate isconcentrated. After removing the solvent in vacuo, 0.4 g (25%) of methyl2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylateremains as a residue having a concentration of 77%.

[0253] Y: 25% =0.4 g (GC. 77% strength), C₂₂H₂₀FNO₄S, MW=413.47;

[0254] Mp.: 191.0° C.

[0255] IR (NaCl): 1/λ (cm⁻¹)=1716, 1693, 1595, 1527, 1311, 1221, 1150,1097, 778, 556,

[0256]¹H-NMR (CDCl₃): δ (ppm)=7.74-7.69 (AA′, 2H, arom), 7.22-6.95 (m,6H, BB′+F-arom), 4.42 (t, 2H, J=7 Hz, CH₂), 3.646 (s, 3H, OCH₃), 3.055(t, 2H, J=7 Hz, CH₂), 3.03 (s, 3H, SO₂CH₃), 2.594 (quin, 2H, J=7 Hz);

[0257] GC-MS: m/e (rel. int.[%])=413(M^(+), 100%), 382 ((MOCH₃ ^())⁺,14%), 355 (10%), 274(12%).

[0258] d) Methyl4-[2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolizin-1-yl]phenyl Sulphone

[0259] Methyl2-(4-fluorophenyl)-1-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate(0.4 g, 0.96 mmol) is heated under reflux for 1 h in methanolic KOH (2N, 9 ml, 1.01 g of KOH, 18 mmol). After cooling, water (20 ml) is addedand the alkaline phase is rendered weakly acidic (pH 3) using HCl (conc.25%). The deposited substance is extracted with ethyl acetate, and theethyl acetate extract is dried using Na₂SO₄ sicc. and concentrated afterfiltering. After the removal of the solvent in vacuo, 0.4 g (75% GC) ofresidue remains. The CC purification is carried out on SiO₂ using ethylacetate as an eluent. The main fractions are concentrated in vacuo andthe residue is recrystallized from diisopropyl ether:

[0260] Y: 17% =0.06 g (gc 95%), C₂₀H₁₈FNO₂S, MW=355.43;

[0261] IR (NaCl): 1/λ (cm⁻¹)=2924, 1593, 1535, 1308, 1219, 1149, 954,839, 776, 554, 537;

[0262]¹H-NMR (CDCl₃/DMSO-d₆): δ (ppm)=7.78-7.74 (AA′.2H, SO₂CH₃.arom-7);7.34-6.9 (m, BB′, 2H, SO₂CH₃ arom-7, +m, 4H, F-arom), 6.73 (s, 1H,pyrroliz.); 4.045 (t, 2H, CH₂, J=7.1); 3.087-2.95 (m, 5H, CH₂, CH₃,);2.60 (quin., 2H, CH₂);

[0263] GC-MS: m/e (rel. int.[%])=355 (M^(+), 100%), 276, 248, 220.

EXAMPLE 8

[0264]2-(4-Fluorophenyl)-1-(4-methanesulphonylphenyl)-3-methyl-6.7-dihydro-5H-pyrrolizine

[0265] a) 6-(4-Fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0266] According to the procedure of Laufer et al. (J. Med. Chem. 1994,37, 1894-1897), first 2-bromo-1-(4-fluorophenyl)ethanone (10.8 g, 0.05mol) in portions and then NaHCO₃ (5.0 g, 0.06 mol) are added to asolution of 2-benzylpyrroline (Example 1a, 15 g, 80%, 0.075 mol) inethanol (150 ml) in a round-bottomed flask. The reaction mixture isstirred for 24-60 h with exclusion of light; during this time thetemperature of the solution is kept between 30-40° C.

[0267] The crystals depositing are filtered off, washed a number oftimes with cold EtOH and dried. 11 g of crude product are obtained,which still contains inorganic salts.

[0268] Y: <79%, NaBr, NaHCO₃, C₁₉H₁₆FN, MW=277.34;

[0269] IR (NaCl): 1/λ (cm⁻¹)=3447, 3040, 2949, 2888, 1596, 1534, 1496,1396, 1213, 1155, 839, 766, 701;

[0270]¹H-NMR (CDCl₃): δ (ppm)=7.26-7.13 (m, 9Harom), 6.74 (s,1H, CH═C),4.05-3.98 (t, 2H, CH₂), 3.01-2.93 (t, 2H, CH₂), 2.56-2.49 (quin, 2H,CH₂);

[0271]¹³C-NMR (CDCl₃): δ (ppm)=161.18 (d, C—F, J=242 Hz), 136.19 (d,J=2.0 Hz), 132.63 (d, J=3.2 Hz), 129.73 (d, J=7.7 Hz), 128.52, 128.11,126.34, 124.946, 114.88 (d, J=21.0 Hz), 113.74, 112.96 (pyrrole-C—H),46.48, 27.34, 24.51.

[0272] b)2-[2-(4-Fluorophenyl)-1:-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]aceticAcid

[0273] Laufer et al. (J. Med. Chem. 1994, 37, 1894-1897)

[0274] Oxalyl dichloride (11.4 g, 0.09 mol) is added dropwise to anice-cold solution of6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (see above 16.6g, 0.06 mol) in THF (100 ml) at 0-10° C. After addition is complete, themixture is stirred for a further hour and ice water (30 ml) is thencautiously added dropwise, which leads to strong evolution of gas and tothe foaming of the mixture. The gases (HCl, CO, CO₂) are led through anabsorber. Hydrazine (36.5 ml, 37.5 g, 0.6 mol) is added dropwise anddiethylene glycol (72 ml) is poured in.

[0275] The reaction mixture is heated to 100° C.; THF and water passover under atmospheric pressure in a distillation bridge. Afterincreasing the temperature in the bottom to 105° C., foaming commences.The mixture is cooled and potassium hydroxide solution (50% in water (44g), 62.8 g of KOH 85%, 1.32 mol) is added at 30-40° C. in 5 portions andthe temperature is increased in steps. At 50-60° C., the evolution ofgas (N2) again commences (take care, strong foaming). At 135° C. (IT),water and residual solvents pass over (H₂O). This temperature ismaintained in the bottom for approximately 2 h, then the evolution ofgas subsides and the colour of the mixture lightens. If the mixture hasreached a pale beige coloration, the batch is poured onto ice. Thereaction mixture is acidified to pH 2-3 using HCl 10% strength (175 g,150 ml of HCl 32%, water 300 ml), while the temperature is kept below10° C. by cooling with ice in order to suppress the decomposition of theproduct.

[0276] The product, which deposits from the acidic solution in the formof fine crystals, is filtered off and washed with water (pH of the washsolutions >5.0).

[0277] If the product deposits oil, it is extracted with ethyl acetate(3×100 ml), dried using Na₂SO₄ sicc., and the filtrate is concentrated.13 g (65%) of oily residue are obtained, which crystallizes fromdiisopropyl ether.

[0278] Y: 65% =13 g (2%), C₂₁H₁₈FNO₂, MW=335.38;

[0279] IR(NaCl): 1/λ (cm⁻¹)=3436, 1721, 1600, 1530, 1501, 1393, 1222,1181, 1156, 839, 699;

[0280]¹H-NMR (CDCl₃): δ (ppm)=7.25-6.93 (m, 9H, arom), 4.06-3.99 (t, 2H,—CH₂), 3.61 (s, 3H, —CH₃), 3.08-3.01 (t, 2H, —CH₂), 2.59-2.52 (quin, 2H,—CH₂).

[0281] c)6-(4-Fluoropbenyl)-5-methyl-7-phenyl-2,3-dihydro-H1-pyrrolizine

[0282] A flask filled with crystalline solid substance of2-[2-(4-fluorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-2-aceticacid (61 g, 0.182 mol) is heated to 180° C. in an oil bath. Thedecarboxylation via the release of CO₂ gas is checked by means of a gasbubble counter; it is complete after 10-15 min. The bath is removed, thecontents are cooled to 50° C. and diisopropyl ether (100 ml) is added.The suspension is stirred until it has cooled to room temperature, thenthe crystals are filtered off with suction and the product iscrystallized again from diisopropyl ether if required.

[0283] 46 g (86.7%) of crystalline compound are obtained.

[0284] Y: 86.7% =46 g (2%), C₂₀H₁₈FN, MW=291.37;

[0285] IR (NaCl): 1/λ (cm⁻¹)=2880, 1599, 1538, 1500, 1218, 829, 700;

[0286]¹H-NMR (CDCl₃): δ (ppm)=7.25-6.90 (m, 9H, arom), 3.94 (t, 2H,J=7.0 Hz, CH₂), 3.036 (t, 2H, J=7.0 Hz, CH₂), 2.54 (quin, 2H, J=7.0 Hz,CH₂), 2.227 (s, 3H, CH₃).

[0287] d)2-(4-Fluorophenyl)-1-(4-methanesulphonylphenyl)-3-methyl-6,7-dihydro-5H-pyrrolizine

[0288] Chlorosulphonic acid (7 g, 60 mmol) is added dropwise to asolution of6-(4-fluorophenyl)-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (2.91 g,10 mmol) in CHCl₃ (12 ml) cooled to 0° C. with further cooling and themixture is heated under reflux (66° C.) for 3 h after addition iscomplete. The reaction mixture is then poured onto ice water (0.4 kg)and the sulphonyl chloride depositing is taken up in chloroform (150ml). The ice-water phase is extracted with chloroform (100 ml). TheseCHCl₃ extracts are dried using Na₂SO₄ sicc. and concentrated. Theresidue is treated with an aqueous solution (25 ml) of Na₂SO₃ (1.42 g,11.2 mmol) and NaHCO₃ (1.89 g, 22.5 mmol) and heated at 70° C. (IT) for2 h. After addition of ethanol (25 ml) and methyl iodide (1.0 ml, 2.27g, 16 mmol), the temperature is increased to 1 00° C. (IT) andmaintained for a further 2 h (reflux). After the cooling of the mixture,deposited solid is filtered off with suction, washed with water (10 ml)and dried over P₂O₅ in vacuo: 0.4 g (11%) of the product having amelting point of 191° C. (97% purity) results. The aqueous-ethanolicphase is extracted with ethyl acetate (50 ml) and the filtrate isconcentrated after drying with Na₂SO₄ sicc. The residue crystallizesfrom EtOH (5 ml): 0.5 g (14% of theory, 94% purity) results.

[0289] Y: 25% =0.9 g, C₂₁H₂₀FNO₂S, MW=369.46;

[0290] Mp: 190-192° C.;

[0291] IR (NaCl): 1/λ (cm⁻¹)=3440, 2975, 2925, 1591, 1533, 1500, 1302,1215, 1152, 844, 772;

[0292]¹H-NMR (CDCl₃): δ (ppm)=7.72-7.68 (AA′, 2H, arom), 7.25-7.00 (m,6H, arom), 3.97 (t, 2H, CH₂), 3.07 (t, 2H, CH₂), 3.00 (s, 3H, SO₂CH₃,),2.65-2.5 (quin, 2H, CH₂), 2.02 (s, 3H, CH₃).

EXAMPLE 9

[0293]2-(4-Fluorophenyl)-3-(4-methanesulphanylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine

[0294] a) 2-Ethyl-1-pyrroline

[0295] (analogously to Example 1, steps a and b)

[0296] Sodium hydride (60% in paraffin, 36 g, 0.9 mol) is suspended inabs. THF (180 ml) in a 1 l three-necked flask having a dropping funneland reflux condenser, and the suspension is heated under gentle refluxfor 10 min. A mixture of ethyl propionate (33.7 g, 0.33 mol) and1-vinyl-2-pyrrolidone (33.34 g, 0.3 mol) in abs. THF (35 ml) is addeddropwise to the boiling suspension (10 min) and kept under reflux for3.5 h by heating with stirring.

[0297] After cooling to 10° C. (ice bath), the excess of sodium hydrideis destroyed (beware! H₂) and neutralized using saturated ammoniumchloride solution (300 ml), and to drive off the liberated ammonia themixture which is now 30° C. is intensively stirred for a further 10 min.The deposited THF phase is separated, dried over Na₂SO₄ sicc. andconcentrated. The paraffin layer depositing on the oil phase isdecanted. The red oily product fraction obtained(3-propionyl-1-vinyl-2-pyrrolidone, 51.2 g, 102% of theory) is usedwithout further purification for the preparation of 2-ethyl-1-pyrroline:

[0298] Y: 102% =51.2 g (about 92%), C₉H₁₃NO₂, MW=167.21;

[0299] Bp: 140.20° C. (760 Torr);

[0300] IR (NaCl): 1/λ (cm⁻¹)=2955, 2925, 2854, 698, 1633, 1456, 1427,1387, 1327, 1273, 1114, 979;

[0301]¹H-NMR (CDCl₃): δ (ppm)=7.08-6.95 (CH), 4.52-4.42 (CH₂), 3.74-3.67(CH), 3.60-3.41 (CH₂), 3.13-2.96 (CH), 2.69-2.51 (CH₂), 2.23-2.09 (CH),1.12-1.04 (t, CH₃);

[0302]¹³C-NMR (CDCl₃): δ (ppm)=205.3 (C═O), 168.4 (C═O), 129.1 (C—H),95.6 (CH₂), 55.2 (C—H), 43.1 (CH₂), 35.9 (CH₂), 19.3 (CH₂), 7.3 (CH₃).

[0303] HCl (20%, 300 ml) is heated to gentle boiling in a 111 3-neckedflask having a dropping funnel as well as a water separator having areflux condenser. A solution of the crude3-propionyl-1-vinyl-2-pyrrolidone (40.4 g, 240 mmol) in THF (60 ml) isadded dropwise (10 min) from the dropping funnel, and the startingmixture is kept at 100° C. (IT). The acetaldehyde/THF mixture (47 ml)collected in the water separator is discarded. The mixture is kept atthis temperature for 6 h, cooled and extracted with ether (200 ml). The2-ethyl-1-pyrroline is deposited in the cold (5-10° C.) from theHCl-acidic aqueous phase by rendering alkaline to pH 9-10. The depositedoil is taken up in diethyl ether (150 ml), and the aqueous phase isextracted with diethyl ether (300 ml). The ether phases are combined,dried (K₂CO₃) and concentrated in a weak vacuum (240 mmnHg, 45° C.).18.4 g (79%) of ethyl-1-pyrroline are obtained as a yellow-coloured oil.

[0304] Y: 79% =18.4 g (about 94%), C₆H₁₁N, MW=97.16;

[0305] Bp: 109.5 (760 mmnHg);

[0306] IR(NaCl): 1/λ (cm⁻¹)=3378, 2969, 2937, 2870, 1644, 1462, 1454,1431, 1371, 1300, 1144, 1093, 1019, 961;

[0307]¹H-NMR (CDCl₃): δ (ppm)=3.38-3.76 (m, CH₂), 2.52-2.34 (m, 2 CH₂),1.95-1.83 (quin, CH₂, J=7.8 Hz), 1.19-1.12 (t, CH₃, J=7.6 Hz);

[0308]¹³C-NMR (CDCl₃): δ (ppm)=179.8, 60.5, 36.9, 26.8, 22.4, 10.6.

[0309] b) 6-(4-Fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine

[0310] 2-Bromo-1-(4-fluorophenyl)-1-ethanone (19.53 g, 90 mmol) is addeddropwise to the oily ethyl-1-pyrroline (17.55 g, 180 mmol) in portionsin a 500 ml flask, the exothermically reacting mixture being cooledbetween the additions. The mixture of the reaction components is heatedin an oil bath (100° C.) with stirring (30 min). The course of thereaction is monitored by TLC.

[0311] The cooled mixture is treated with CH₂Cl₂ (250 ml), and depositedsalts are washed out in the separating funnel using two portions of HCl(3%, 40 ml). The CH₂Cl₂ phase is washed with water (50 ml), dried(Na₂SO₄ sicc.) and concentrated.

[0312] As a residue, 14.04 g (72% of theory) of6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine remain as a brownviscous oil.

[0313] Y: 72% =14.04 g (about 90%), C₁₄H₁₄FN, MW=215.27;

[0314] IR (NaCl): 1/λ (cm⁻¹)=2958, 1703, 1601, 1509, 1223, 1158, 839,755;

[0315]¹H-NMR (CDCl₃): δ (ppm) 7.39-7.30 (m, 2H, F-arom), 7.08-6.98 (m,2H, F-arom), 6.67 (s, 1H, 5-H), 3.954 (t, 2H, CH₂, J=7 Hz), 2.801 (t,2H, CH₂, J=7 Hz), 2.487 (quin, CH₂, J=7 Hz), 2.125 (s, 3H, CH₃);

[0316]³C-NMR (CDCl₃): δ (ppm)=161.04 (d, C—F, J=242 Hz), 135.58 (d,J=2.0 Hz), 133.51 (d, J=2 Hz), 128.87 (d, J=7.5 Hz), 127.65, 115.025 (d,J=20.9 Hz), 111.11 (pyrrole-C—H), 106.71, 46.47, 27.44, 23.14, 10.86;

[0317] GC-MS: m/e (rel. int.[%])=216 (14), 215 (M^(+), 100%), 214 (99),201 (7), 200 (40), 199 (7), 198 (10), 172 (10) 146 (10).

[0318] c) 5-Bromo-6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine

[0319] The solution of6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine (9.0 g, 42 mmol)in abs. THF (50 ml) is cooled to −15° C. N-Bromosuccinimide (3.46 g,19.4 mmol) is added in portions; the mixture is stirred until no morestarting material is detectable (TLC SiO₂, diisopropyl ether-hexane2:1).

[0320] The black-purple-coloured reaction mixture is chromatographed ona column (20 cm×3 cm) packed with Al₂O₃ (ICI, for dry packing). Thecolumn is subsequently washed with n-hexane (80 ml), and the filtratesare concentrated. 3.55 g (28.9%) of a black-brown oil are obtained,which rapidly decomposes.

[0321] Y: 28.9% =3.55 g (about 90%), C₁₄H₁₄FN, MW=215.27;

[0322]¹H-NMR (CDCl₃): δ (ppm)=7.37-7.29 (m, 2H, F-arom), 7.15-7.00 (m,2H, F-arom), 3.923 (t, 2H, CH₂, J=7 Hz), 2.861 (t, 2H, CH₂, J=7 Hz),2.482 (quin, CH₂, J=7 Hz), 2.006 (s, 3H, CH₃).

[0323] d)2-(4-Fluorophenyl)-3-(4-methanesulphanylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine

[0324] (according to Suzuki et al., J. Heterocyclic Chem. 31, 1637(1994))

[0325] 5-Bromo-6-(4-fluorophenyl)-7-methyl-2,3-dihydro-1H-pyrrolizine(2.66 g, 8.83 mmol) and tetrakis-(triphenylphosphine)palladium (330 mg,0.29 mmol, 1:30) are dispersed in toluene (12 ml), the solution of4-methylthiophenylboronic acid (1.0 g, 6 mmol) in EtOH (7.5 ml) is addedand Na₂CO₃ solution (12 ml, 2 M, 2.8 g) is finally added. The mixture ofthe components is immersed in an oil bath maintained at 100° C. andrefluxed until the disappearance of the bromo compound (16 h). Theblack-coloured mixture is treated with saturated NaCl solution (50 ml)and CH₂Cl₂ (80 ml). The organic phase is separated and concentrated invacuo, and the residue is purified by CC (AM₂O₃, diisopropyl ether,n-hexane 1:3). The residue obtained from fractions 7-18 is crystallizedfrom n-hexane: 0.58 g (28%) of2-(4-fluorophenyl)-3-(4-methanesulphanylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizinehaving a melting point of 113.7° C.

[0326] Y: 28% =0.58 g, C₂₁H₂₀FNS, MW=337.46;

[0327] IR (NaCl): 1/λ (cm⁻¹)=2985, 2918, 2842, (1596) 1524, 1504, 1479,1424, 1404, 1367, 1305, 1215, 830, 805;

[0328]¹H-NMR (CDCl₃): δ (ppm)=7.2-6.9 (8H, m, arom), 4.0 (2H, t, J=6.9Hz), 2.88 (2H, t, J=7.3 Hz), 2.501 (2H, quin, CH₂), 2.45 (3H, s, CH₃),2.03 (3H, s, CH₃);

[0329]³C-NMR (CDCl₃): δ (ppm)=161.1 (d, C—F, J=240 Hz), 137.52, 135.76,132.59 (d, J=3.2 Hz), 131.60 (d, J=4 Hz, CH), 129.83, 129.06 (CH),126.32 (CH), 124.87, 114.94 (d, J=21 Hz, CH), 108.50 (C-5), 46.32 (CH₂),27.26 (CH₂), 23.29 (CH₂), 15.69 (SCH₃), 10.23 (7-CH3).

[0330] GC-MS (70 eV): m/z (rel. int. [%])=339 (5), 338 (27), 337 (100,M+.), 336 (25), 322 (40), 290 (10).

[0331] e)2-(4-Fluorophenyl)-3-(4-methanesulphinylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine

[0332] CC (SiO₂, EA/n-hexane 4:1):

[0333] Fraction 1-2:

[0334]2-(4-Fluorophenyl)-3-(4-methanesulphonylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine

[0335] Fraction 3-5

[0336]2-(4-Fluorophenyl)-3-(4-methanesulphinylphenyl)-1-methyl-6,7-dihydro-5H-pyrrolizine

[0337]¹H-NMR (CDCl₃): δ (ppm)=7.52-7.47 (AA′, 2H, Ar.), 7.29-7.24 (BB′,2H, Ar.), 7.16-7.10 (m, 2H, F-arom), 7.09-6.92 (m, 2H, F-arom), 4.04(2H, t, J=6.9 Hz), 2.89 (2H, t, J=7.3 Hz), 2.73 (s, 3H, SOCH₃), 2.53(2H, quin, CH₂), 2.02 (3H, s, CH₃).

[0338] f)2-(4-Fluorophenyl)-3-(4-methanesulphonylpbenyl)-1-methyl-6.7-dihydro-5H-pyrrolizine

[0339] CC (SiO₂, EA/n-hexane 4:1):

[0340]¹H-NMR (CDCl₃): δ (ppm)=7.77-7.72 (AA′, 2H, Ar.), 7.29-7.24 (BB′,2H, Ar.), 7.16-7.10 (m, 2H, F-arom), 7.09-6.92 (m, 2H, F-arom), 4.06(2H, t, J=6.9 Hz), 3.05 (s, 3H, SO₂CH₃), 2.90 (2H, t, J=7.3 Hz), 2.54(2H, quin, CH₂), 2.01 (3H, s, CH₃).

EXAMPLE 10

[0341]4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0342] a) 1-(4-Fluorobenzoyl)pyrrolidine-2-carboxylic Acid

[0343] L-Proline (2.5 g, 22 mmol) is dissolved in NaOH (5%, 25 ml, 31mmol) and, after cooling, treated dropwise, with vigorous stirring, with4-fluorobenzoyl chloride (3.17 g, 20 mmol). The resulting suspension isagain treated with NaOH (5%, 15 ml, 19 mmol) and stirred at RT for 1 h.HCl (20% strength, 10 ml) is added with ice cooling and the mixture isstirred until formation of a crystallizate which can be filtered offwith suction. The crystallizate subsequently filtered off with suctionis washed with water until HCl-free and dried over P₂O₅ in a desiccator.

[0344] 4.21 g (88.8% of theory) of crystallizate remain after drying.

[0345] Y: 89% (4.21 g), C₁₂H₁₂FNO₃, MW=237.23;

[0346] Mp: 174.0° C.;

[0347] IR(NaCl): 1/λ (cm⁻¹)=1735, 1605, 1585, 1514, 1440, 1230, 1180,1161, 856, 762, 513;

[0348]¹H-NMR (CDCl₃): δ (ppm)=7.64-7.61 (d, 2H, J=5.4 Hz), 7.59-7.57 (d,2H, J=5.4 Hz), 7.16-7.07 (t, 2H, J=8.6 Hz).

[0349] b) Methyl3-(4-fluorophenyl)-2-phenyl-6.7-dihydro-5H-pyrrolizine-1-carboxylate

[0350] Methyl phenylpropiolate (methyl dehydrocinnamate (0.96 g, 6mmol)) is dissolved in acetic anhydride (14 ml) and brought to theboiling temperature of acetic anhydride in a hot oil bath (140° C.). Thetotal amount of 1-(4-fluorobenzoyl)pyrrolidine-2-carboxylic acid (1.42g, 6 mmol) is added, and the thoroughly mixed solution is refluxed (128° C.) for 20 h with stirring. After standing for 4 hours and coolingto RT, a pure crystalline solid deposits (TLC: Al₂O₃, diisopropyl ether,Rf 0.7). The crystals are filtered off with suction, washed with water(20 ml) and finally with isopropyl ether (10 ml). The dried crystalsweigh 650 mg (32.5% of theory)

[0351] Y: 89% (4.21 g), C₂₁H₁₈FNO₂, MW=335.38;

[0352] IR(NaCl): 1/λ (cm⁻¹)=2497, 1791, 1493, 1428, 1157, 846;

[0353]¹H-NMR (CDCl₃): δ (ppm)=7.50-7.37 (m, 6H), 7.17-7.01 (r, 2H,F-arom), 3.93-3.86 (t, 2H), 3.53 (s, CH₃), 3.01-2.94 (t, 2H), 2.55-2.41(m, 2H).

[0354] c)4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0355] In a dried flask which has been flushed with argon and cooled to−15° C. in a cooling bath with exclusion of moisture, chlorosulphonicacid (2.6 ml, 4.537 g, 39 mmol) is treated in 2 portions with ethyl3-(4-fluorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-1-carboxylate(436 mg, 1.3 mmol). The mixture is stirred for 16 h, the cooling isremoved and it is warmed to RT. The reaction is monitored by TLC(SiO₂/isopropyl ether-EA 1:1, starting material Rf 0.8, sulphochlorideRf 0.7). Excess chlorosulphonic acid and resultant H₂SO₄ are quenchedafter cooling to −15 to −20° C. by dropwise addition of water (20 ml)and the sulphuric acid aqueous phase is extracted with ethyl acetate (60ml). The combined, dried (Na₂SO₄ sicc.) EA phases are saturated with NH₃in a cooling bath (−15° C.) (10 min) and subsequently stirred at RT fora further 2 h (TLC checking: SiO₂/isopropyl ether-EA 1:1, startingmaterial Rf 0.8, sulphochloride Rf 0.7, sulphonamide Rf 0.0; RP18/acetone —H_(20 7:3), starting material Rf 0.2, sulphochloride Rf 0.1,sulphonamide Rf 0.4). The semi-solid residue depositing is digested withMeOH (10 ml), the insoluble ammonium salts are filtered off and theclear solution is concentrated in vacuo. The residue obtained (0.55 g)is digested with ether, and the solid substance obtained from ether invacuo is recrystallized from ethanol: 0.45 g (97% of theory) remains.

[0356] Y: 89% (4.21 g), C₁₉H₁₇FN₂O₂S, MW=356.42;

[0357] Mp: 206.9° C.;

[0358] IR(NaCl): 1/λ (cm⁻¹)=3355, 3048, 1596, 1403, 1321, 1151;

[0359]¹H-NMR (CD₃OD): δ (ppm)=7.58-7.81 (d, 1H, J=8.4 Hz), 7.66-7.62 (d,1H, J=8.5 Hz), 7.59-7.56 (d, 1H, J=5.3 Hz), 7.54-7.52 (d, 1H, J=5.3 Hz),7.16-7.07 (t, 2H, J=8.8 Hz), 6.74 (s, 1H), 4.19-4.12 (t, 2H, J=7.1 Hz),3.18-3.10 (t, 2H, J=7.2 Hz), 2.68-2.55 (m, 2H);

[0360]¹³C-NMR (CD₃OD): δ (ppm)=163.4, 158.6, 139.7, 138.4, 136.7, 128.7,128.5, 127.1, 127.0, 126.2, 124.2, 115.4, 115.0, 114.2, 108.0, 46.1,27.3, 25.2.

EXAMPLE 11

[0361] Ethyl3-(4-fluorophenyl)-2-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0362] a) Ethyl 2-bromo-3-(4-methylsulphanylphenyl)acrylate

[0363] 4-Methylsulphanylbenzaldehyde (1.52 g, 10 mmol), dissolved intoluene (8 ml), is rapidly added dropwise to a solution ofbromoethoxycarbonyltriphenylphosphoranylidene (4.48 g, 10.5 mmol) intoluene (30 ml) with exclusion of light (aluminium foil wrapping). Themixture is stirred overnight at RT (16 h, TLC checking:SiO₂/ether-hexane 1:1). Toluene is removed in vacuo, the residue isdigested with diethyl ether (50 ml), and the residual crystalprecipitate (triphenylphosphine oxide) is washed 2 times with ether (15ml). The ether filtrates are concentrated in vacuo and the crude product(5.7 g) is purified by column chromatography (SiO₂/ether-hexane 7:3):2.72 g result.

[0364] Y: 90%, C₁₂H₁₃BrO₂S MW=301.20;

[0365]¹H-NMR (CDCl₃): δ (ppm)=8.16 (s, 1H), 7.85-7.80 u; 7.28-7.24(AA′BB′, 4H, arom), 4.404.29 (q, J=7.1 Hz, 2H), 2.51 (s, CH₃), 1.42-1.35(t, J=7.1 Hz, CH₃).

[0366] b) Ethyl3-(4-fluorophenyl)-2-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0367] A solution of ethyl 2-bromo-3-(4-methylsulphanylphenyl)acrylate(0.75 g, 3 mmol) in acetic anhydride (7 ml) is treated withN4-fluorobenzoylproline (0.59 g, 2.5 mmol), and the reaction vessel isimmersed in an oil bath maintained at 150° C. The mixture is refluxedfor 18 h with stirring; it is then allowed to cool. After about 48 h,the starting solution is treated with ice water and the acetic acidaqueous phase is extracted with ethyl acetate. The ethyl acetate phasewashed with water is dried with Na₂SO₄ sicc. and concentrated in arotary evaporator. The residue obtained (1.0 g) is purified by CC(SiO₂/ether-hexane 1:1): two products are isolated: fractions 11-13 (Rf0.5) afford 20 mg, fractions 15-25 (Rf 0.3) 15 mg. ⅔ (0.49 g) of theethyl 2-bromo-3-(4-methylsulphanylphenyl)acrylate used is recovered infractions 6-8.

[0368] Product A:

[0369] Ethyl3-(4-fluorophenyl)-2-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0370] Y: 20 Mg, C₂₃H₂₂FNO₂S, MW=395.50;;

[0371]¹H-NMR (CDCl₃): δ (ppm)=: 8.01-7.94 u. 6.98-6.89 (m, 4H, arom),7.13 (s, 5H), 4.17-4.08 (q u. t, 4H), 4.02-3.95 (t, J=7.1 Hz, 2H),3.25-3.17 (t, J=7.5 Hz, 2H), 2.61-2.47 (quin, J=7.4 Hz, 2H), 2.31 (s,CH₃), 1.24-1.16 (t, J=7.2 Hz, CH₃).

[0372] Product B:

[0373] Ethyl3-(4-fluorophenyl)-1-(4-methylsulphanylphenyl)-6,7-dihydro-5H-pyrrolizine-2-carboxylate

[0374] Y: 15 mg, C₂₃H₂₂FNO₂S, MW=395.50;

EXAMPLE 12

[0375] Ethyl3-(4-fluorophenyl)-2-(4-methylsulphonylphenyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0376] a) 4-Methylsulphonylbenzaldehyde

[0377] A solution of 4-methylmercaptobenzaldehyde (6.08 g, 40 mmol) inCH₂Cl₂ (40 ml) is cooled to 5° C. in an ice bath. A solution ofm-chloroperbenzoic acid (mCPBA, 19.72 g, 70% strength, 80 mmol) in CHCl₃(220 ml) is added dropwise, the reaction temperature being kept below10° C. (1 h). The mixture is stirred for 4 h in an ice bath. Thecrystallized m-chlorobenzoic acid (14 g) is filtered off with suction.The filtrate is first washed with NaHCO₃ solution (8% strength, 50 ml)until acid-free (m-chlorobenzoic acid 5 g) and then rewashed with water(100 ml). The CHCl₃ phase dried over Na₂SO₄ sicc. is concentrated invacuo until a white solid substance deposits. The solid deposited fromthe cooled mother liquor is collected (5.26 g).

[0378] Y: 75% (5.26 g), C₈H₈O₃S, MW=184.22;

[0379] Mp: 160.5-162.1° C.;

[0380] IR (NaCl): 1/λ (cm⁻¹)=3000, 2925, 1702, 1294, 1148, 961, 766,529;

[0381]¹H-NMR (CDCl₃): δ (ppm)=10.15 (s, CHO), 8.17-8.13 u. 8.11-8.07(AA′BB′, 4H, arom), 3.11 (s, CH₃);

[0382]¹³C-NMR (CDCl₃): δ (ppm)=190.6, 145.3, 139.6, 130.3, 128.2, 44.3.

[0383] b) Ethyl 2-bromo-3-(4-methylsulphonylphenyl)acrylate

[0384] The suspension of 4-methylsulphonylbenzaldehyde (3.68 g, 20 mmol)in toluene (30 ml) is added with the exclusion of light to a solution ofbromoethoxycarbonyltriphenylphosphoranylidene (8.55 g, 20 mmol) intoluene (60 ml). The mixture is first stirred overnight at RT (16 h, TLCchecking: SiO₂/ether-hexane 1:1), then heated at 60° C. for 6 h and,after addition of bromoethoxycarbonyl-triphenylphosphoranylidene (2.0 g,5 mmol), stirred for a further 24 h, this is repeated again (2.0 g, 5mmol) and the mixture is finally worked up after a further 24 h. Tolueneis removed in vacuo, the residue is digested with diethyl ether (40 ml),and the remaining crystal precipitate (triphenylphosphine oxide) issuspended 2 times with ether (10 ml) and filtered off with suction. Theether filtrates are concentrated in vacuo, and the crude product iscrystallized from diisopropyl ether (5 ml): 2.3 g of white solidsubstance result which, however, contain 4-methylsulphonylbenzaldehyde(25%).

[0385] Y: 25.9% (2.3 g, 75% strength), C₁₂H₁₃BrO₄S, MW=333.20;

[0386]¹H-NMR (CDCl₃): δ (ppm)=8.24 (s, 1H), 7.99 (s, 5H), 4.44-4.33 (q,J=7.1 Hz, 2H), 3.09 (s, CH₃), 1.44-1.37 (t, J=7.1 Hz, CH₃).

[0387] or: Ethyl 2-bromo-3-(4-methylsulphanylphenyl)acrylate (Example11a, 0.9 g, 3 mmol) is dissolved in CHCl₃, and the solution is cooled to5° C. and then treated dropwise with a CHCl₃ solution (20 ml) of mCPBA(1.65 g, 70%, 6.6 mmol). The mixture is stirred for 3 h in the cold andthen for 16 h at RT, then the deposited solid is filtered off withsuction and washed with CHCl₃ (20 ml). The CHCl₃ filtrates are firstwashed with NaHCO₃ solution (8% strength, 50 ml) until acid-free(m-chlorobenzoic acid 5 g) and then rewashed with water (100 ml). TheCHCl₃ phase dried over Na₂SO₄ sicc. is completely concentrated in vacuo:a white solid substance of 1.03 g (103%) remains, which contains smallamounts of impurity.

[0388] c) Ethyl3-(4-fluorophenyl)-2-(4-methylsulphlylphenyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate

[0389] A solution of ethyl 2-bromo-3-(4-methylsulphonylphenyl)acrylate(0.67 g, 2 mmol) in acetic anhydride (4 ml) is treated withN-4-fluorobenzoylproline (0.47 g, 2 mmol), and the reaction vessel isimmersed in an oil bath maintained at 150° C. The mixture is refluxedfor 72 h with stirring; it is then allowed to cool. The black-colouredstarting solution is concentrated in vacuo, the residue is taken up inethyl acetate (20 ml) and the acetic acid-containing ethyl acetatesolution is first washed with NaHCO₃ solution (10% strength, 20 ml)until acid-free. The ethyl acetate phase then washed with water (20 ml)is dried using Na₂SO₄ sicc. and concentrated in a rotary evaporator. Theresidue obtained (1.0 g) is purified by CC (Al₂O₃/ether-THF 9:1):fraction {fraction (11/12)} (Rf 0.75) affords 20 mg of product A. Theethyl 2-bromo-3-(4-methylsulphonylphenyl)acrylate (0.5 g) employed isrecovered in fractions 2-8 (Rf 0.8) and 170 mg of theN-4-fluorobenzoylproline in fractions 15-31 (Rf 0.5).

[0390] Y: 20 mg, C₂₃H₂₂FNO₄S MW=427.50;

[0391]¹H-NMR (CDCl₃): δ (ppm)=7.80-7.76 u. 7.43-7.38 (AA′BB′, 4H, arom),7.09-6.96 (m, 4H, arom), 4.23-4.12 (q, J=7. IHz, 2H), 4.03-3.96 (t,J=7.2 Hz, 2H), 3.27-3.19 (t, J=7.4 Hz, 2H), 3.05 (s, CH₃), 2.63-2.49(quin, J=7.2 Hz, 2H), 1.26-1.19 (t, J=7.0 Hz, CH₃).

EXAMPLE 13

[0392] {4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]phenyl}Methyl Sulphone

[0393] a) Methyl [4-(2-nitrovinyl)phenyl] Sulphone

[0394] A mixture of 4-methylsulphonylbenzaldehyde (1.84 g, 10 mmol),nitromethane (1.0 ml, 1.134 g, 18.5 mmol), anhydrous ammonium acetate(1.5 g, 19 mmol) and glacial acetic acid (7.0 ml) is refluxed at 120° C.for 3 h. The mixture is treated with water (20 ml) and extracted threetimes with ether (30 ml). The collected ether phase is first washed withNaHCO₃ solution (10% strength, 20 ml) until acid-free. The ether phasesubsequently washed with water (20 ml) is dried using Na₂SO₄ sicc. andconcentrated in a rotary evaporator. Yield: 54.0% (1.23 g).

[0395] or

[0396] A mixture of 4-methylsulphonylbenzaldehyde (22.08 g, 120 mmol)and nitromethane (12.5 ml, 14.2 g, 233 mmol) in MeOH (1 1) is cooled to3° C. in an ice bath; sodium hydroxide solution (32%, 420 ml, 567 g, 135g of NaOH, 3.36 mol) is then added dropwise, a clear solution beingformed after addition of 30 ml (time needed 1 h). The mixture is stirredat 10° C. for 2 h and then added dropwise at 10° C. to initiallyintroduce HCl (20%, 1080 ml, 216 g of HCl, 5.9 mol) (time needed 40min). The HCl-acidic mixture is stirred until formation of theprecipitate is complete (30 min). The nitrostyrene crystallizate isfiltered off with suction, washed with ice water until the wash phasegives a neutral reaction and dried over P₂O₅ in an evacuated desiccator.The yield of crystallizate is 16.03 g after drying.

[0397] Y: 58.8% (16.03 g), C₉H₉NO₄S, MW=227.24;

[0398] IR (NaCl): 1/λ (cm⁻¹)=3105, 1640, 1520, 1341, 1308, 1148, 956,773, 664, 547;

[0399]¹H-NMR (CDCl₃): δ (ppm)=8.07-8.02 u. 7.77-7.73 (AA′BB′, 4H, arom),8.035/7.645 (AB, J=14 Hz, 2H, CH═CH), 3.10 (s, CH₃).

[0400] b) {4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]phenyl}Methyl Sulphone

[0401] A solution of N-4-fluorobenzoylproline (11.08 g, 46.7 mmol) inacetic anhydride (4 ml) is maintained at 80° C. IT in an oil bath.Methyl [4-(2-nitrovinyl)phenyl] sulphone (9.66 g, 42.5 mmol) is added,and the reaction vessel is immersed in an oil bath maintained at 150° C.The mixture is refluxed for 4 h with stirring; after the evolution ofCO₂ has subsided, it is allowed to cool. The black-coloured startingsolution is taken up in ethyl acetate (200 ml), and the aceticacid-containing ethyl acetate solution is washed with Na₂CO₃ solution(10% strength, 20 ml) until acid-free. The ethyl acetate phasesubsequently washed with saturated NaCl solution (200 ml) is dried usingNa₂SO₄ sicc. and concentrated in a rotary evaporator. The residueobtained (22.6 g) is taken up in ethyl acetate (30 ml) and purified byCC (Al₂O₃/ether): fractions 4-7 (Rf 0.75) afford 1.45 g of product A,and fractions 8/9 (Rf 0.75+Rf 0.6) are a mixed fraction and affordproducts A+B. The structural isomer B (0.88 g) is obtained in fractions10-14 (Rf 0.6).

[0402] Product A:{4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]phenyl} MethylSulphone

[0403] Y: 8.7% (1.45 g), C₂₀H₁₈FNO₂S, MW=355.43;

[0404] Mp: 153.7° C.;

[0405] IR (NaCl): 1/λ (cm)=1591, 1525, 1509, 1301, 1223, 1148, 1091,956, 843, 769, 547;

[0406]¹H-NMR (CDCl₃): δ (ppm)=7.75-7.71 u. 7.39-7.35 (AA′BB′, 4H,-pyridyl), 7.28-7.21 (m, 2H, arom), 7.10-7.01 (m, 2H, arom), 6.12 (s,CH), 3.94-3.88 (t, J=6.9 Hz, CH₂), 3.04 (s, CH₃), 2.99-2.92 (t, J=7.3Hz, CH₂), 2.59-2.44 (quin, J=7.2 Hz, CH₂);

[0407]¹³C-NMR (CD₃OD): δ (ppm)=164.6, 159.6, 143.0, 137.7, 136.4, 131.2,131.0, 128.8, 128.7, 128.0, 127.4, 125.1, 124.1, 116.1, 115.6, 100.2,45.9, 44.6, 27.4, 24.5.

[0408] Product B:{4-[3-(4-Fluorophenyl)-6,7-dihydro-5H-pyrrolizin-1-yl]phenyl} MethylSulphone

[0409] Y: 5.3% (0.88 g), C₂₀H₁₈FNO₂S, MW=355.43;

[0410] Mp: 176.00-179.00° C.,

[0411] IR (NaCl): 1/λ (cm⁻¹)=1594, 1525, 1488, 1302, 1223, 1146, 1092,971, 959, 836, 791, 769;

[0412]¹H-NMR (CDCl₃): δ (ppm)=7.91-7.86 u. 7.66-7.61 (AA′BB′, 4H,-pyridyl), 7.48-7.41 (m, 2H, arom), 7.16-7.05 (m, 2H, arom), 6.67 (s,CH), 4.18-4.11 (t, J=7.1 Hz, CH₂), 3.20-3.13 (t, J=7.3 Hz, CH₂), 3.07(s, CH₃), 2.72-2.57 (quin, J=7.2 Hz, CH₂);

[0413]¹³C-NMR (CD₃OD): δ (ppm)=164.1, 159.2, 142.0, 137.6, 135.7, 129.3,129.0, 128.9, 127.9, 127.7, 127.6, 125.1, 116.0, 115.5, 114.5, 108.9,46.6, 44.7, 27.8, 25.8.

EXAMPLE 14

[0414]4-[2-Cyclohexyl-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0415] a) Ethyl 1-acetylcyclohexanecarboxylate

[0416] Ethyl acetoacetate (52.06 g, 0.40 mol) and 1,5-dibromopentane(92.0 g, 0.40 mol) are mixed in a 200 ml 3-necked flask and maintainedat 80° C. in an oil bath. An Na ethoxide solution (21%, 245 g, 0.75 mol)is added dropwise from a dropping funnel over the course of 45 min, thetemperature then being kept between 70 and 80° C. for 1 h. A GC sampleshows a starting material/by-product/product ratio of 1:4:13, altogethera proportion of 18% of the acid cleavage product ethylcyclohexane-carboxylate.

[0417] Water (100 ml) is added and a water/ethanol mixture (200 ml) isremoved in vacuo, the mixture is cooled to RT and water (100 ml) isagain added. The mixture is extracted with diethyl ether (250 ml) andthe phases are separated. The aqueous phase is extracted 2 times withdiethyl ether (150 ml), and the ether phase combined with there-extracts is washed with satd. NaCl solution (100 ml). The etherealproduct solution is dried over Na₂SO₄ sicc. and concentrated in vacuo.

[0418] The oil fraction obtained (92 g, 116%) contains the desiredproduct in a concentration of 65% (GC). Isolation is carried out byfractional distillation: the fraction obtained between 83-90° C./0.3 bar(33 g) contains the compound sought in 90% purity (yield: 38%)

[0419] Y: 41.5% =33 g (90% strength), C₁₁H₁₈O₃, MW=198.26;

[0420] Bp: 52.00 (0.075 mmHg);

[0421] IR (NaCl): 1/λ (cm⁻¹)=2938, 2858, 1735, 1712, 1452, 1361, 1303,1214, 1133;

[0422]¹H-NMR (CDCl₃): δ (ppm)=4.254.15 (q, CH₂, J=7.1 Hz), 2.15 (s,CH₃), 2.11-1.40 (m, 10H, cyclohex.), 1.30-1.23 (t, CH₃, J=7.1 Hz);

[0423]¹³C-NMR (CDCl₃): δ (ppm)=205.6, 172.2, 61.1, 30.5, 25.8, 25.2,22.7, 14.0.

[0424] b) Ethyl 1-bromoacetylcyclohexanecarboxylate

[0425] Ethyl 1-acetylcyclohexanecarboxylate (2.2 g, 90% strength, 10mmol) is dissolved in abs. CH₂Cl₂ (10 ml). A solution of bromine (1.6 g,10 mmol) in CH₂Cl₂ (3 ml) is added dropwise to the solution in thecourse of 45 min. The mixture is freed from liberated HBr by stirringintensively for 3 hours (GC sample). The reaction solution isneutralized using 5 ml of semi-saturated NaHCO₃ solution and the CH₂Cl₂phase separated in a separating funnel is dried over Na₂SO₄ sicc. andconcentrated in vacuo. A residue of 3.08 g (111%) remains, whichaccording to GC analysis contains 78.8% of product (86.8% yield) and1,5-dibromopentane from the preceding reaction as an impurity.

[0426] Y: 111% =3.1 g (78.8% strength), C₁₁H₁₇BrO₃, MW=277.16;

[0427] Bp: 98.00 (0.0005 mmHg);

[0428] IR (NaCl): 1/λ (cm⁻¹)=2939, 2858, 1735, 1720, 1451, 1304, 1221,1137, 1022;

[0429]¹H-NMR (CDCl₃): δ (ppm)=4.24-4.13 (q, CH₂, J=7.2 Hz), 4.11 (s,CH₂), 2.11-1.37 (m, 10H, cyclohex.), 1.28-1.21 (t, CH₃, J=7.2 Hz);

[0430]³C-NMR (CDCl₃): δ (ppm)=198.6, 171.5, 61.6, 60.4, 31.8, 30.9,25.0, 22.6, 14.0.

[0431] c) Ethyl1-(1-phenyl-6,7-dihydro-5H-pyrrolizin-2yl)cyclohexanecarboxylate

[0432] A mixture of 2-benzyl-1-pyrroline (11.65 g, 60 mmol) and ethyll-bromoacetylcyclohexanecarboxylate (15.2 g, 78.8% strength, 45 mmol) isheated at 100° C. for 1.5 h without solvent; 2-benzyl-1-pyrroline (5.82g, 30 mmol) is then again added and the temperature is kept at 100° C.for a further hour. The mixture is cooled and the melt residue is takenup in CH₂Cl₂ (200 ml) and extracted twice with dilute HCl (3% strength,200 ml). The HCl-acidic phase is backwashed with CH₂Cl₂ (100 ml) and thecombined CH₂Cl₂ solutions are dried over Na₂SO₄ sicc. and concentratedto 50 ml in vacuo. This concentrate is transferred to a short column ofAl₂O₃ (neutral, for TSC, ICI), and the column is then eluted with amixture of CH₂Cl₂ and n-hexane (1:2, 250 ml). The eluate is concentratedto dryness in vacuo; the residue contains 12.6 g of the product (86.9%of theory) in 90% purity.

[0433] Y: 87% =12.6 (90% strength), C₂₂H₂₇NO₂, MW=337.47;

[0434] IR(NaCl): 1/λ (cm⁻¹)=2935, 2857, 1720, 1450, 1298, 1214, 1129,702;

[0435]¹H-NMR (CDCl₃): δ (ppm)=7.35-7.16 (5H, arom), 6.58 (s, 1H),4.01-3.85 (m, 2×CH₂), 2.71-2.63 (t, CH₂), 2.49-2.32 (q, CH₂), 2.25-2.14(CH₂), 1.69-1.22 (m), 1.19-1.12 (t, CH₃);

[0436]¹³C-NMR (CDCl₃): δ (ppm)=176.3, 138.1, 135.9, 130.6, 129.7, 127.4,125.8, 114.8, 111.4, 60.2, 47.6, 46.7, 35.6, 27.0, 25.8, 23.8, 23.3,14.0.

[0437] d)1-(3-Carboxymethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)cyclohexanecarboxylicAcid

[0438] A solution of ethyl1-(1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)cyclohexanecarboxylate (2.03g, 5.5 mmol) in abs. THF (10 ml) is treated under argon with one drop oftriethylamine; a solution of oxalyl dichloride (1.12 g, 8.8 mmol) in THFabs. (2 ml) is then added dropwise in small portions while cooling in anice bath and the mixture is subsequently stirred after the addition fora further 30 min (TLC: SiO₂, ether-n-hexane (1:1): starting material Rf0.8, product 0.4). Without isolation of the oxalyl chlorideintermediate, hydrazine hydrate (80% strength, 3.8 ml, 60 mmol) is thenadded dropwise over the course of 30 min. The reaction mixture is firstheated to an IT of 85° C. in an oil bath and THF (11 ml) issimultaneously distilled over via a distillation bridge. After coolingto about 50° C., diethylene glycol (7.0 ml) and, in small portions, KOH(6.3 g, 112 mmol) are added. The mixture is slowly heated to 140° C. insteps (oil bath 180° C.). While initial residual THF, water (3 ml) andexcess hydrazine distill over, a reaction temperature of 140-150° C. isachieved after about 30 min, which is maintained for 3 h.

[0439] The mixture is cooled, water (20 ml) is added at 80° C. and it isrendered acidic (pH 2.0, ice bath cooling) using HCl 20% strength. Thelight yellow solid depositing is filtered off with suction and washedwith 10 ml of ice water until the wash water gives a neutral reaction.After drying in a desiccator (P₂O₅), 2.14 g (87% of theory) ofdicarboxylic acid remain.

[0440] Y: 87% =2.1 g (92% strength), C₂₂H₂₅NO₄, MW=367.45;

[0441] Mp: 147.00-157.00° C.;

[0442] IR (NaCl): 1/λ (cm⁻¹)=2930, 2856, 1703, 1602, 1450, 1079, 702;

[0443]¹H-NMR (CDCl₃): δ (ppm)=9.14 (COOH), 7.27-7.23 (m, arom 5H),3.90-3.83 (t, CH₂, J=6.8 Hz), 3.79 (s, CH₂), 2.64-2.57 (t, CH₂, J=7.1Hz), 2.43-2.33 (m, CH₂), 2.19-2.12 (m, 2H), 1.62-1.10 (m, 10H,cyclohex.);

[0444]³C-NMR (CDCl₃): δ (ppm)=181.8, 177.5, 139.7, 134.9, 131.0, 127.7,126.1, 124.8, 117.0, 115.3, 61.8, 49.5, 35.8, 33.4, 29.7, 26.4, 25.8,24.2, 23.8, 19.9.

[0445] e) 6-Cyclohexyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0446]1-(3-Carboxymethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)cyclohexanecarboxylicacid (1.5 g, 3.7 mmol) is immersed in an oil bath of 150° C. for 30 minin a 25 ml flask. The release of CO₂ is checked via a bubble counter.The still warm melt is digested with diisopropyl ether (15 ml). Theinsoluble crystalline residue is filtered off with suction and dried.0.84 g (82% of theory) of decarboxylation product6-cyclohexyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (TLC: SiO₂,ether-n-hexane (1:1): starting material Rf 0-0.2, product 0.9) isobtained.

[0447] Y: 82% =0.8⁴ g (97% strength), C₂₀H₂₅N, MW=279.43;

[0448] Mp: 107.30° C.;

[0449] IR (NaCl): 1/λ (cm⁻¹)=2926, 2849, 1602, 1446, 1423, 1378, 1301,1087, 1071, 767, 689;

[0450]¹H-NMR (CDCl₃): δ (ppm)=CDCl₃: 7.39-7.15 (m, arom 5H), 3.90-3.83(t, CH₂, J=7.0 Hz), 2.91-2.84 (t, CH₂, J=7.3 Hz), 2.49-2.42 (t, CH₂,J=7.2 Hz), 2.30 (s, CH₃), 1.84-1.60 u. 1.29-1.19 (m, 101H, cyclohex.);

[0451]¹³C-NMR (CDCl₃): δ (ppm)=CDCl₃: 137.7, 131.4, 129.2, 128.0, 126.4,124.8, 118.9, 114.8, 44.4, 36.0, 33.4, 27.3, 126.7, 26.3, 24.4, 22.9,11.9.

[0452] f)4-(2-Cyclohexyl-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl)benzenesulphonamide

[0453] 6-Cyclohexyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (0.56g, 2 mmol) is stirred into chlorosulphonic acid (1.0 ml, 1.745 g, 15mmol) at RT. After a reaction time of 3 h (TLC: SiO₂, ether-n-hexane(1:1): starting material Rf 0.9, intermediate Rf 0.7), the mixture isheated at 80° C. for a short time (30 min) and cooled again. CHCl₃ (15ml) is added and ice water (15 ml) is cautiously added dropwise. Thephases are separated and the aqueous sulphuric acid phase is extracted afurther 5 times with CHCl₃ (10 ml). The CHCl₃ phase is dried over Na₂SO₄sicc. and a stream of dry NH₃ is passed into the solution over thecourse of 30 min (TLC: SiO₂, ether-n-hexane (1:1): intermediate Rf 0.7,final product Rf 0.3). The mixture is stirred for a further 60 min,filtered and concentrated in vacuo (crude yield 210 mg, 29% of theory,light beige substance). The residue is dissolved in hot EtOH (9 ml) andrecrystallized in the cold again after addition of water (4 ml). 106 mg(14.9%) of 98.7% product having a melting point of 256.2° C.crystallize.

[0454] Y: 15% =0.1 g (99% strength), C₂₀H₂₆N₂O₂S, MW=358.51

[0455] Mp: 256.20;

[0456] IR (NaCl): 1/λ (cm⁻¹)=3343, 3232, 2926, 2849, 1595, 1334, 1161,1094, 735, 548;

[0457]¹H-NMR (CDCl₃): δ (ppm)=7.91-7.86 u. 7.39-7.35 (AA′BB′, 4H, arom),4.78 (s, NH₂), 3.91-3.84 (t, CH₂, J=7.0 Hz), 2.93-2.85 (t, CH₂, J=7.3Hz), 2.56-2.46 (m, CH₂), 2.30 (s, CH₃), 1.81-1.59 u. 1.27-1.21 (m, 10H,cyclohex.);

[0458]¹³C-NMR (CDCl₃): δ (ppm)=143.0, 137.4, 132.5, 129.2, 126.4, 119.8,113.4, 44.6, 36.1, 33.3, 27.3, 26.7, 26.2, 24.6, 11.9.

EXAMPLE 15

[0459]4-[2-(4-Fluorophenyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0460] A flask containing chlorosulphonic acid (84.2 g, 0.72 mol) iscooled to 0-5° C.2-(4-Fluorophenyl)-3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizine (Example8 d, 35 g, 0.12 mol) is stirred in in 7 portions in the course of 1.5 hunder a dry argon atmosphere. HCl is immediately released. The mixtureis stirred further at RT for a further 30 h. The reaction mixture isthen quenched in ice water (0.4 kg). The sulphonyl chloride depositingis taken up in CHCl₃ (150 ml), and the ice-water phase is extracted withCHCl₃ (2×50 ml). These CHCl₃ extracts are dried using Na₂SO₄ sicc.

[0461] The dried CHCl₃ solution of the sulphonyl chloride is made up(800 ml) with dry CHCl₃ (CaCl₂ sicc.) and transferred to a flask.Ammonia (dried over NaOH) is introduced into the dilute solution, whichis cooled in an ice water bath to an internal temperature of 0-10° C.,from a pressurized container. After complete saturation of the solutionwith NH₃, the white suspension formed is stirred at low temperature(5-10° C.) for a further 3 h. The mixture is then poured into ice water(300 ml) and stirred. The organic phase is then separated in aseparating funnel and washed twice with water (200 ml), dried overNa₂SO₄ sicc. and concentrated in vacuo after filtration. The residue iscrystallized from methanol. The crystals are collected, washed withdiisopropyl ether and dried. 12.5 g (27%) of product remain.

[0462] Y: 27% =12.5 g (94%), C₂₀H₁₉FN₂O₂S, MW=370.45;

[0463] Mp: 120.0° C.;

[0464] IR (NaCl): 1/λ (cm⁻¹)=3350, 3266, 1595, 1538, 1501, 1220, 1160,836, 604, 549;

[0465]¹H-NMR (CDCl₃): δ (ppm)=7.71-7.67 (AA′,2H, arom), 7.25-6.94(BB′+AA′BB′, 6H, arom), 4.79 (s, 2H, CH₂), 3.99-3.92 (t, 2H, CH₂),3.08-3.0 (t, 2H, CH₂), 2.64-2.5 (quin 2H, CH₂), 2.2 (s, 3H, CH₃).

EXAMPLE 16

[0466]4-[3-Chloro-2-(4-fluorophenyl)-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0467] a)5-Chloro-6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0468] The clear solution of6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 8 d,2.77 g, 10 mmol) in THF (20 ml) is treated at RT withN-chlorosuccinimide (NCS, 1.34 g, 10 mmol). The solution, immediatelyturning from yellow to black-coloured with spontaneous heating, isstirred for a further 10 min, then adsorbed on an Al₂O₃ column (100 g,TSC—ICI), and the substance sought is eluted with ethyl acetate-n-hexane1:9 (Rf=0.8, starting material Rf=0.6). The eluate fractions areconcentrated in vacuo and the residue is crystallized from diisopropylether: 1.63 g (52%)

[0469] Y: 52% (1.63 g), C₁₉H₁₅ClFN, MW=311.79;

[0470] Mp: 127° C.;

[0471] IR (NaCl): 1/λ (cm⁻¹)=1601, 1530, 1490, 1400, 1294, 1219, 836,783, 736, 705;

[0472]¹H-NMR (CDCl₃): δ (ppm)=7.25-6.93 (m, 9H, arom), 4.01 (t, 2H,J=7.1 Hz, CH₂), 3.04 (t, 2H, J=7.3 Hz, CH₂), 2.54 (quin, 2H, J=7.2 Hz,CH₂);

[0473]¹³C-NMR (CDCl₃): δ (ppm)=163.9, 159.0, 135.4, 133.5, 131.6, 131.4,130.3, 130.2, 128.3, 128.2, 125.2, 121.0, 115.2, 114.7, 45.5, 26.7,25.3.

[0474] b)4-[3-Chloro-2-(4-fluorophenyl)-67-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0475] 5-Chloro-6-(4-fluorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine(1.39 g, 4.5 mmol) is added in portions (5) to chlorosulphonic acid(3.75 g, 32.2 mmol) cooled to 0° C. in the flask and the mixture isstirred at RT for 16 h. The black-coloured mixture is diluted with CHCl₃(25 ml) and cautiously poured onto ice (40 ml). The CHCl₃ phase isseparated in a separating funnel; the aqueous phase and emulsion layerare extracted twice with CHCl₃ (80 ml). The H₂O phase and emulsion layerare saturated with NaCl and extracted with ethyl acetate.

[0476] The CHCT₃ extract is dried over Na₂SO₄ sicc., cooled to 2° C. inan ice bath and saturated with N13 from a pressurized container (30min). The saturated solution is stirred for 1 h, the ammonium chloridecrystallized from the reaction mixture is filtered off with suction, andthe filtrate is concentrated. The residue (0.52 g, 89% purity)crystallizes from ethanol: 0.27 g (15%).

[0477] Y: 15% (0.27 g), C₁₉H₁₆ClFN₂O₂S, MW=390.87;

[0478] Mp: (162° C. dec;

[0479] IR (NaCl): 1/λ (cm⁻¹)=3376, 3269, 1597, 1529, 1396, 1329, 1224,1163, 1087, 839;

[0480]¹H-NMR (CDCl₃+DMSO-d₆): δ (ppm)=7.75-7.71 and 7.33-7.00 (m, 8H,arom), 5.30 (s, 2H, NH₂), 4.03 (t, 2H, J=7.1 Hz, CH₂), 3.05 (t, 2H,J=7.3 Hz, CH₂), 2.58 (quin, 2H, J=7.1 Hz, CH₂);

[0481]³C-NMR (CDCl₃/DMSO-d₆): δ (ppm)=163.8, 158.9, 139.7, 138.9, 134.5,131.4, 131.3, 129.7, 129.6, 127.9, 126.0, 120.9, 115.3, 114.8, 113.4,45.5, 39.4, 26.4, 25.4.

EXAMPLE 17

[0482]4-[2-(4-Chlorophenyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0483] a) 6-(4-Chlorophenyl)-7-:phenyl-2,3-dihydro-1H-pyrrolizine

[0484] (according to Laufer et al. J. Med. Chem. 1994, 37, 1894-1897)2-Benzyl-1-pyrroline (Example 1 a, 19.8 g, 80% strength, 0.1 mol),dissolved in MeOH (300 ml) is treated with 4-chlorophenacyl bromide(23,4 g, 0.1 mol) and then with NaHCO₃ (10 g, 0.12 mol) and stirred atRT for 16 h with exclusion of light. Precipitated crystallizate isfiltered off with suction and washed with MeOH. 16.4 g (56%) of productare obtained after drying.

[0485] Y: 56% (16.4 g), C₁₉H₁₆ClN, MW=293.80;

[0486] Mp: 142.0° C.; C₁₉H₁₆ClN, MW=293.80;

[0487] IR (NaCl): 1/λ (cm⁻¹)=3447, 2983, 2879, 1600, 1524, 1485, 1401,1187, 1088, 1010, 837, 765, 701;

[0488]¹H-NMR (CDCl₃): δ (ppm)=7.26-7.13 (m, 9H, arom), 6.748 (s, 1H,—CH═C), 4.026 (t, sH, J=7.2 Hz, CH₂), 2.980 (t, 2H, J=7.4 Hz, CH₂),2.536 (quin, 2H, CH₂, J=7.2 Hz).

[0489] b)2-[2-(4-Chlorophenyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]acetic Acid

[0490] according to Laufer et al. J. Med. Chem. 1994, 37, 1894-1897

[0491] Oxalyl dichloride (2.8 g, 0.0225 mol) is added dropwise to anice-cold solution of6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (see above, 4.35g, 0.015 mol) in TIF (50 ml) at 0-10° C. After addition is complete, themixture is stirred for 15 min and the excess of acid chloride is thencautiously decomposed (gas and foam formation!) using ice water (30 ml).Hydrazine (9.5 ml, 80%, 0.15 mol) is added dropwise, the mixture isstirred for 30 min and diethylene glycol (18 ml) is poured in. THF andwater are distilled off under atmospheric pressure at a bath temperatureof 100-110° C. (foam formation from 105° C.!). The mixture is cooled to60° C. and potassium hydroxide solution (50% in water, 15.7 g of KOH85%, 0.238 mol) is added in 5 portions, the temperature is increased insteps to 140° C. (foam formation!) and water and residual solvents aredriven off. This temperature is maintained in the bottom until theevolution of gas subsides (1 h) and the colour of the mixture lightens.The mixture cooled to 60° C. is poured onto ice (300 g) and acidified topH 2-3 with conc. HCl with ice-cooling (temp. <10° C.).

[0492] The product depositing is extracted with ethyl acetate (150 ml),washed with water until neutral, dried using Na₂SO₄ sicc. andconcentrated at 45° C. in the presence of heat until the start ofcrystallization. The crystal mass deposited at 5° C. is filtered offwith suction and washed with cold ethyl acetate and dried.

[0493] Y: 46% =2.4 g (%), C₂₁H₁₈ClNO₂, MW=351.84;

[0494] Mp: 170° C.;

[0495] IR (NaCl): 1/λ (cm⁻¹)=2950, 1710, 1596, 1418, 1232, 830, 705;

[0496]¹H-NMR (CDCl₃): δ (ppm)=7.27-7.05 (m, 9H, arom), 6.74 (s, 1H,—CH═C), 4.06-3.99 (t, 2H, J=7.0 Hz, CH₂), 3.60 (s, 2H, CH₂), 3.03 (t,2H, J=7.0 Hz, CH₂), 2.61 (quin, 2H, J=7.0 Hz, CH₂).

[0497] c)6-(4-Chlorophenyl)-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0498] A flask, filled with crystalline solid substance of2-[2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-2-aceticacid (1.8 g, 0.005 mol), is heated at 180° C. in an oil bath until theCO₂ release checked by a gas bubble counter subsides (10-15 min). Theresidue cooled to 50° C. is stirred with diisopropyl ether (50 ml) untilit has cooled to room temperature, then the undissolved crystals arefiltered off with suction and the crude product is crystallized againfrom diisopropyl ether if required.

[0499] 1.0 g (64%) of white, crystalline compound are obtained.

[0500] Y: 64% =1.0 g (99%), C₂₀H₁₈ClN, MW=307.83;

[0501] IR (NaCl): 1/λ (cm⁻¹)=3447, 2943, 1600, 1532, 1415, 1116, 708;

[0502]¹H-NMR (CDCl₃): δ (ppm)=7.255-7.04 (m, 9H, arom), 3.94 (t, 2H, J=7Hz, CH₂), 3.03 (t, 2H, CH₂), 2.54 (quin, 2H, J=7 Hz, CH₂), 2.236 (s, 3H,CH₃).

[0503] d)4-[2-(4-Chlorophenyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0504] 6-(4-Chlorophenyl)-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine(0.8 g, 0.0026 mol) is added to chlorosulphonic acid (1.87 g, 0.0167mol), cooled to 0° C. in the flask and the mixture is stirred at RT for5 h. The chlorosulphonic acid is cautiously destroyed with water (10 ml)while cooling in an ice bath, and resultant sulphuric acid is diluted.Resultant sulphochloride is extracted with ethyl acetate (50 ml), andthe extract is dried over Na₂SO₄ sicc. and concentrated. The residueremaining after evaporation of the solvent in vacuo is taken up in dryCHCl₃ (CaCl₂), and the CHCl₃ solution is saturated with NH₃ from apressurized container. The saturated solution is stirred for 2 h,saturated again with NH₃ and, after stirring for a further 2 hours, theammonium chloride crystallized from the reaction mixture is filtered offwith suction. The filtrate is concentrated and the residue iscrystallized from diethyl ether: 0.4 g (40%).

[0505] Y: 40% =0.4 g (97%), C₂₀H₁₉ClN₂O₂S, MW=386.90;

[0506] IR (NaCl): 1/λ (cm⁻¹)=3336, 3260, 1596, 1433, 1426, 1315, 1160,1118, 1093, 836, 727, 603, 548;

[0507]¹H-NMR (CDCl₃): δ (ppm)=7.72 (d, 2H, arom), 7.27-7.04 (m, 6H,arom), 3.99-3.92 (t, 2H, CH₂), 3.06-2.99 (t, 2H, CH₂), 2.64-2.54 (quin,2H, CH₂), 2.21 (s, 3H, CH₃).

EXAMPLE 18

[0508] Ethyl2-(4-chlorophenyl)-1-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0509] a) Ethyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0510] 6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml) is treated with 1 dropof triethylamine (about 50 mg). A solution of diphosgene (0.5 g, 2.5mmol), dissolved in THF (5 ml) is added dropwise to this solution at RTand it is stirred for 8 h.

[0511] Ethanol (abs., 3 ml) is then added, and the mixture is stirred atRT for a further 12 h. The solvent is completely removed in vacuo (45°C.), and the residue is washed with water (5 ml) and finallyrecrystallized from a little diisopropyl ether.

[0512] Y (after drying): 87.1% (1.62 g), C₂₂H₂₀ClNO₂, MW=365.86;

[0513] Mp: 143.7° C.;

[0514] IR (NaCl): 1/λ (cm⁻¹)=2985, 2969, 1694, 1545, 1473, 1415, 1385,1311, 1221, 1126, 1097;

[0515]¹H-NMR (CDCl₃): δ (ppm)=7.28-7.17 (m, 5H, arom), 7.14-6.91(AA′BB′, 4H, arom), 4.40 (t, CH₂), 4.10 (q, OCH₂), 3.00 (t, CH₂), 2.55(quin, CH₂), 1.15 (t, CH₃).

[0516] b) Ethyl2-(4-chlorophenyl-1-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0517] Ethyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(1.6 g, 4.4 mmol) is added in 4 portions to the chlorosulphonic acid(8.0 ml, 14.0 g, 120 mmol) cooled to −10° C. and protective gas isintroduced. After stirring at RT for 15 h, the mixture is diluted withdry CH₂Cl₂ (100 ml), and a stream of NH₃ gas is passed in from apressurized container until it is saturated. The suspension of ammoniumsalts is subsequently stirred for a further 2 h and then treated withwater (200 ml). A weakly acidic pH (pH 5.0) is set using dil. HCl (10%)and the phases are separated. The aqueous phase is extracted with ethylacetate (100 ml). The combined organic phases are dried over Na₂SO₄sicc., and the solvent mixture is removed in vacuo. The residue obtainedis crystallized from ethanol (1.8 g, 92.3%).

[0518] Y: 92.3% (1.8 g), C₂₂H₂₁ClN₂O₄S, MW=444.94;

[0519] Mp: dec 320° C.;

[0520] IR (NaCl): 1/λ (cm⁻¹)=3248, 2980, 1589, 1518, 1375, 1311, 1163;

[0521]¹H-NMR (CD₃OD): δ (ppm)=7.63-7.59 (AA′, 2H, arom), 7.27-7.11(BB′+AA′, 4H, arom), 7.08-7.04 (BB′, 2H, arom), 4.86 (s, SONH₂), 4.37(t, 2H, CH₂), 4.08 (q, 2H, OCH₂), 3.03 (t, 2H, CH₂), 2.65 (quin, 2H,CH₂), 1.09 (t, 3H, CH₃).

EXAMPLE 19

[0522] Methyl2-(4-chlorophenyl)-1-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0523] a) Methyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0524] 6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated with 1 dropof triethylamine (about 50 mg). A solution of diphosgene (0.5 g, 2.5mmol), dissolved in THF (5 ml), is added dropwise to this solution at RTand it is stirred for 8 h. Methanol (abs., 3 ml) is then added, and themixture is stirred at RT for a further 12 h. The solvent is completelyremoved in vacuo (45° C.). The resinous residue is dissolved in CHCl₃(20 ml) and washed twice with water (20 ml). After the removal of thesolvent in vacuo, a residue which is recrystallized from a littlediisopropyl ether is obtained from the CHCl₃ phase dried using Na₂SO₄sicc. Y: 99.5% (1.98 g), C₂₁H₁₈ClNO₂, MW=351.84;

[0525] IR (NaCl): 1/λ (cm⁻¹)=2947, 1630, 1463, 1396, 1227, 1013, 708;

[0526]¹H-NMR (CDCl₃): δ (ppm)=7.25-7.11 (m, 7H, arom), 7.01-6.91 (BB′,2H, arom), 4.39 (t, 2H, CH₂), 3.65 (s, 3H, CH₃), 3.02 (t, 2H, CH₂), 2.56(quin, 2H, CH₂).

[0527] b) Methyl2-(4-chlorophenyl)-1-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0528] Methyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(0.87 g, 2.5 mmol) is dissolved in dichloroethane (10 ml) and thesolution is cooled to 0-5° C. in an ice bath. A solution ofchlorosulphonic acid (0.5 g, 5.7 mmol) in dichloroethane (5 ml) isslowly added dropwise (IT<10° C.), and the mixture is then stirred at RTfor 12 h. A solution of NH₃ in dichloroethane saturated in the cold isadded, and the mixture is stirred at RT for a further 12 h. The mixtureis then treated with water (20 ml), and the organic phase is separatedin a separating funnel. Solid which is insoluble in water is filteredoff from the aqueous phase with suction and dried in vacuo. The driedsolid substance is crystallized from MeOH: 0.5 g (47%); a 2nd crystalfraction crystallized from the mother liquor in the cold: 23% (0.25 g).

[0529] Y: 70.5% (0.75 g)+, C₂₁,H₁₉ClN₂O₄S, MW=430.91;

[0530] IR(NaCl): 1/λ (cm⁻¹)=3448, 3177, 1693, 1463, 1452, 1440, 1397,1313, 1221, 1186, 1134, 1095, 1036, 1008;

[0531]¹H-NMR (CD₃OD): δ (ppm)=7.63-7.59 (AA′, 2H, arom), 7.26-7.10(AA′BB′, 4H, arom), 7.06-7.02 (BB′, 2H, arom), 4.87 (s, SONH₂), 4.37 (t,2H, CH₂), 3.62 (s, 3H, COOCH₃), 3.02 (t, 2H, CH₂), 2.56 (quin, 2H, CH₂).

EXAMPLE 20

[0532]4-[2-(4-Chlorophenyl)-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0533] a) Benzyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0534] 6-(4-Chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example17 a, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated withtriethylamine (0.7 ml, 0.51 g, 5 mmol). A solution of diphosgene (0.5 g,2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solutionat RT, and it is stirred for 8 h. Benzyl alcohol (abs., 0.52 ml, 0.54 g)and triethylamine (0.7 ml, 0.51 g, 5 mmol) are then added, and themixture is stirred at RT for a further 48 h. The reaction mixture ispartitioned between water (30 ml) and diethyl ether (60 ml), and theether phase is washed with NaOH (5%, 20 ml). An oily residue is obtainedfrom the THF/ether phase dried using Na₂SO₄ sicc. after the removal ofthe solvent in vacuo.

[0535] Y: 55% (1.2 g), C₂₇H₂₂ClN0₂, MW=427.93;

[0536] IR (NaCl): 1/λ (cm⁻¹)=2956, 1685, 1600, 1515, 1465, 1305, 1224,1133;

[0537]¹H-NMR (CDCl₃): δ (ppm)=7.24-6.57 (m, 14H arom), 5.11 (s, CH₂),4.443-4.36 (t, CH₂), 3.05-2.98 (t, CH₂), 2.61-2.50 (qu, CH₂).

[0538] b)4-[2-(4-Chlorophenyl)-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0539] Benzyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(0.48 g, 1.1 mmol) is added to an initially introduced amount ofchlorosulphonic acid (2.5 ml, 4.4 g, 38 mmol) which is maintained at−48° C. (>solidification point). After the removal of the cooling bath,the mixture is allowed to warm to RT with stirring; it is stirred herefor a further 24 h. It is then treated with a saturated solution of NH₃in CHCl₃ (30 ml), and the mixture is again stirred for 16 h. Thedeposited salts are taken up in water (30 ml) and the phase mixture isextracted with ethyl acetate (50 ml), dried (Na₂SO₄ sicc.) andconcentrated to 10% of the starting volume. 110 mg (27%) of solidsubstance is crystallized from EA.

[0540] C₁₉H₁₇ClN₂O₂S, MW=372.88;

[0541] IR (NaCl): 1/λ (cm⁻¹)=3427, 2957, 2897, 1596, 1525, 1486, 1393,1219, 1186, 1128, 1011, 835, 635;

[0542]¹H-NMR (CDCl₃): δ (ppm)=7.7-7.66 (AA′, 2H, arom), 7.20-7.10 (m,7H, arom), 4.89 (s, 2H, SONH₂), 4.01 (t, 2H, CH₂), 2.935 (t, 2H, CH₂),2.54 (quin, 2H, CH₂).

EXAMPLE 21

[0543]4-[1-(4-Chlorophenyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0544] a) 2-(4-Chlorobenzyl)-1-pyrroline

[0545] Magnesium turnings (4.04 g, 168 mmol) are introduced into diethylether abs. (10 ml), and the formation of the Grignard reagent is startedwith a crystal of iodine and 4-chlorobenzyl chloride (2.2 ml, 2.7 g,16.8 mmol). The remaining amount of 4-chlorobenzyl chloride (19 ml, 24g, 148.7 mmol), dissolved in diethyl ether abs. (150 ml), is addeddropwise (45 min) such that the mixture boils vigorously. After additionis complete, the mixture is refluxed by heating for a further 1.5 h. Asolution of 4-chlorobutyronitrile (16.6 g, 160 mmol) in diethyl etherabs. (150 ml) is added dropwise to the solution of the 4-chlorobenzylGrignard reagent prepared in this way (45 min), the mixture is stirredfor a further 45 min after the addition, toluene abs. (200 ml) is addedand diethyl ether is distilled off over a bridge until a temperature of95° C. is reached in the bottom (2.5 h). The mixture is cooled in an icebath and dil. HCl (10%) is added at 25-30° C. until a pH of 2-3 isreached in the depositing aqueous phase. The toluene/ether phase isseparated and extracted 3 times with HCl (10%, 150 ml). The collectedHCl phase is washed again with toluene (100 ml) and then renderedalkaline (pH 9-10) with NaOH (32%). The depositing oily pyrroline phaseis taken up in diethyl ether (300 ml), dried over K₂CO₃ andconcentrated. The concentrated ether phase (to 50%-55% product content)is used without further purification.

[0546] Y: 14.1 g (21.6%);

[0547]¹H-NMR (CDCl₃): δ (ppm)=7.25-7.09 (AA′BB′, 4H, arom), (s, 2H,CH₂), 4.035 (t, CH₂), 2.965 (t, CH₂), 2.545 (quin, CH₂).

[0548] b) 7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine

[0549] 2-(4-Chlorobenzyl)-1-pyrroline (9 g, 50% strength, 25 mmol),dissolved in MeOH (75 ml) is treated with phenacyl bromide (4.97 g, 25mmol) and then with NaHCO₃ (2.5 g, 30 mmol) and stirred at RT for 16 hwith exclusion of light. Precipitated crystallizate is filtered off withsuction and washed with MeOH. 3.3 g (45%) of product are obtained afterdrying.

[0550] Y: 45% (3.3 g), C₁₉H₁₆ClN, MW=293.80;

[0551] IR (NaCl): 1/λ (cm⁻¹)=3029, 2970, 2894, 1598, 1524, 1486, 1443,1392, 1295, 1189, 1090;

[0552]¹H-NMR (CDCl₃): δ (ppm)=7.25-7.09 (m, 9H, arom), 6.75 (s, 1H),4.035 (t, CH₂), 2.965 (t, CH₂), 2.545 (quin, CH₂).

[0553] c)2-[1-(4-Chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizin-3:-y]aceticAcid

[0554] Oxalyl dichloride (5.6 g, 0.044 mol) is added dropwise at 0-10°C. to an ice-cold solution of7-(4-chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (9.2 g, 0.031mol) in THF (100 ml). After addition is complete, the mixture is stirredfor 15 min and the excess of acid chloride is then cautiously decomposed(gas and foam formation!) with ice water (12 ml). Hydrazine (18 ml, 80%,about 0.3 mol) is added dropwise, the mixture is stirred for 30 min anddiethylene glycol (36 ml) is poured in. THF and water are distilled offunder atmospheric pressure at a bath temperature of 100-110° C. (foamformation at 105° C.!). The mixture is cooled to 60° C. and potassiumhydroxide (15.7 g of KOH 85%, 0.238 mol) is added in portions and thetemperature in the bottom is increased to 140° C. (foam formation!), andwater, hydrazine and residual solvents are distilled off. Thistemperature is maintained in the bottom for 1 h and the mixture isallowed to cool. The mixture cooled to 60° C. is treated with water (200ml) and acidified to pH 2-3 with conc. HCl in an ice bath (temp. <10°C.). The depositing carboxylic acid is extracted with ethyl acetate (300ml), and the EA extract is washed with water until neutral, dried usingNa₂SO₄ sicc. and concentrated in the presence of heat (45° C.) until thestart of crystallization and placed in the cold. The crystal massdeposited at 5° C. is filtered off with suction and washed with coldethyl acetate and dried.

[0555] Y: 6 g (55%), C₂₁H₁₈ClN0₂, MW=351.84;

[0556] IR (NaCl): 1/λ (cm⁻¹)=3434, 2959, 2903, 1703, 1531, 1489, 1425,1303, 1091, 834, 702, 515;

[0557]¹H-NMR (CDCl₃): δ (ppm)=7.33-6.96 (m, 9H, arom), 4.02 (t, 2H,CH₂), 3.62 (s, 2H, CH₂), 3.02 (t, 2H, CH₂), 2.56 (quin, 2H, CH₂).

[0558] d)7-(4-Chlorophenyl)-5-methyl-6-phenyl-2,3-dihydro-1H-pyrrolizine

[0559] A flask, filled with crystalline solid substance of2-[2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl]-2-aceticacid (1.5 g, 4.3 mmol), is heated at 180° C. in an oil bath until therelease of CO₂ controlled by a gas bubble counter subsides (10-15 min).The residue cooled to 50° C. is stirred with diisopropyl ether (50 ml)until it has cooled to room temperature, then the undissolved crystalsare filtered off with suction and the crude product is crystallized fromdiisopropyl ether.

[0560] 1.1 g of cream-coloured, crystalline compound are obtained.

[0561] Y: 73% (1.1 g), C₂₀H₁₈ClN, MW=307.83;

[0562] Mp.: 120.0° C.;

[0563] IR (KBr): 1/λ (cm⁻¹)=3050, 2970, 2870, 1606, 1535, 1487, 1424,1088, 1010, 829, 766, 701;

[0564]¹H-NMR (CDCl₃): δ (ppm)=7.3-6.98 (m, 9H, arom), 3.94 (t, 2H, CH₂),3.02 (t, 2H, CH₂), 2.54 (quin, 2H, CH₂), 2.24 (s, 3H, CH₃).

[0565] e)4-[1-(4-Chlorophenly)-3-methyl-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0566] 7-(4-Chlorophenyl)-5-methyl-6-phenyl-2,3-dihydro-1H-pyrrolizine(5.4 g, 0.0175 mol) is added in portions (0.5 g) to the chlorosulphonicacid (13 g, 0.112 mol) cooled to 0° C. in the flask, and the mixture isstirred at RT for 18 h. The chlorosulphonic acid is cautiously destroyedwith water (10 ml) while cooling in an ice bath and resultant sulphuricacid is diluted. Resultant sulphochloride is extracted with ethylacetate (50 ml), and the extract is dried over Na₂SO₄ sicc. andconcentrated. The residue remaining after the evaporation of the solventin vacuo is treated with a solution of NH₃ in CHCl₃ (150 ml), which wasobtained by passing in NH₃ at 0° C. until it was saturated. The mixtureis stirred for 1 h, and then the ammonium salts crystallized from thereaction mixture are filtered off with suction. The filtrate isconcentrated and the residue (5.4 g) is purified by CC (SiO₂/EA-n-hexane6:4). After the removal of the solvent, 1.0 g (15%) of the puresubstance is obtained from the product fractions.

[0567] Y: 15% =1.0 g (%), C₂₀H₁₉ClN₂O₂S, MW=386.90;

[0568] IR (KBr): 1/λ (cm⁻¹)=3335, 3255, 1595, 1489, 1340, 1164, 835,749, 547;

[0569]¹H-NMR (CDCl₃): δ (ppm)=7.83-7.79 (d, 2H, arom), 7.28-6.95 (m, 6H,arom), 4.77 (s, 2H, NH₂), 3.99-3.92 (t, 2H, CH₂), 3.03-2.96 (t, 2H,CH₂), 2.63-2.49 (quin, 2H, CH₂), 2.26 (s, 3H, CH₃).

EXAMPLE 22

[0570] Ethyl1-(4-chlorophenyl)-2-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0571] a) Ethyl1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0572] 7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example21 b, 1.5 g, 5.1 mmol), dissolved in THF (10 ml), is treated withtriethylamine (0.7 ml, 0.51 g, 5 mmol). A solution of diphosgene (0.5 g,2.5 mmol), dissolved in THF (5 ml), is added dropwise to this solutionat RT, it is stirred for 12 h, ethanol (abs., 3 ml, 2.37 g, 51 mmol) andtriethylamine (0.7 ml, 0.51 g, 5 mmol) are added, and the mixture isstirred at RT for a further 72 h. The reaction mixture is concentratedin vacuo, and the residue is crystallized from EtOH and dried.

[0573] Y: 81.5% (1.52 g), C₂₂H₂₀ClNO₂, MW=365;

[0574] IR (NaCl): 1/λ (cm⁻¹)=2985, 2969, 1694, 1545, 1473, 1415, 1385,1311, 1221, 1126, 1097;

[0575]¹H-NMR (CDCl₃): δ (ppm)=7.28-7.17 (m, 5H, arom), 7.14-6.91(AA′BB′, 4H, arom), 4.40 (t, 2H, CH₂), 4.10 (q., OCH₂), 3.01 (t, 2H,CH₂), 2.56 (quin, 2H, CH₂), 1.055 (t, 3H, CH₃).

[0576] b) Ethyl1-(4-chlorophenyl)-2-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0577] Ethyl1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(1.6 g, 4.4 mmol) is suspended in chlorosulphonic acid (8 ml, 14.2 g,120 mmol), which has previously been adjusted to a temperature of −10°C., and the mixture is stirred at RT for 16 h; it is then warmed briefly(30 min, 60° C.) and subsequently cooled again. The mixture is treatedwith ice (20 ml) and extracted with CHCl₃ (20 ml). The CHCl₃ phase driedover Na₂SO₄ sicc. is treated with a solution of NH₃ in CHCl₃ (20 ml)saturated in the cold, and the mixture is stirred at RT for a further 12h. The insoluble substance at the bottom is then filtered off withsuction. This residue is heated in 120 ml of ethanol, and undissolvedsalts are filtered off with suction. On concentration of the EtOHsolution to 20% of the starting volume, 1.5 g of product crystallizeout. After further concentration, an additional 170 mg are obtained inthe cold.

[0578] Y: 85.3% (1.67 g), C₂₂H₂₁ClN₂O₄S, MW=444.94;

[0579] Mp: dec from 110°;

[0580] IR(NaCl): 1/λ (cm⁻¹)=3265, 2981, 1688, 1542, 1464, 1419, 1382,1312, 1227, 1163, 1098;

[0581]¹H-NMR (CDCl₃): δ (ppm)=7.73-7.68 (AA′, 2H, arom), 7.27-7.23 (AA′,2H, arom), 7.04-7.00 (BB′, 2H, arom), 6.81-677 (BB′, 2H, arom), 4.31 (t,2H, CH₂), 4.02 (q, 2H, OCH₂), 2.94-2.83 (t, 4H, CH₂+SO₂NH₂), 2.48 (quin,2H, CH₂), 0.99 (t, 3H, CH₃).

EXAMPLE 23

[0582] Methyl1-(4-chlorophenyl)-2-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0583] a) Methyl1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0584] 7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example21 b, 4.0 g, 13.6 mmol), dissolved in THF (25 ml) is treated withtriethylamine (2.0 ml, 1.5 g, 15 mmol). A solution of diphosgene (1.5 g,7.5 mmol), dissolved in THF (15 ml), is added dropwise to this solutionat RT, and it is stirred for 12 h. Methanol (abs., 8.0 ml, 6.3 g, 200mmol) and triethylamine (2.0 ml, 1.5 g, 15 mmol) are then added, and themixture is stirred at RT for a further 48 h. The reaction mixture isconcentrated in vacuo, ammonium salts are taken up in water (10 ml), andthe residue which remains is filtered off with suction and dried. 4.7 g(98.3%) of crude product are obtained.

[0585] Y: 98.3% (4.7 g), C₂₁H₁₈ClNO₂, MW=351.84;

[0586] Mp: 147-149° C.;

[0587] IR(NaCl): 1/λ (cm⁻¹)=2951, 1703, 1545, 1468, 1435, 1405, 1394,1311, 1218, 1162, 1094, 833, 727, 696;

[0588]¹H-NMR (CDCl₃): δ (ppm)=7.25-717 (m, 5H, arom), 7.14-6.89 (AA′BB′,4H, arom), 4.40 (t, 2H, CH₂), 3.63 (s, 3H, COOCH₃), 3.00 (t, 2H, CH₂),2.55 (quin, 2H, CH₂).

[0589] b) Methyl1-(4-chlorophenyl)-2-(4-sulphamoylphenyl)-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0590] Methyl2-(4-chlorophenyl)-1-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(4.0 g, 11.4 mmol) is dissolved in dichloroethane (40 ml), and thesolution is cooled to 0-5° C. in an ice bath. A solution ofchlorosulphonic acid (2.0 g, 17.3 mmol) in dichloroethane (20 ml) isslowly added dropwise to this (IT<10° C., 15 min) and the mixture isthen stirred at RT for 12 h. A solution of NH₃ in dichloroethane (40 ml)saturated in the cold is added, and the mixture is stirred at RT for afurther 12 h. It is then treated (pH 9) with water (20 ml), and theorganic phase is separated in a separating funnel. Solid insoluble inwater is filtered off from the aqueous phase with suction and dried invacuo. The dried solid substance is crystallized from MeOH: 0.76 g(product A).

[0591] The dichloroethane phase is dried over Na₂SO₄ sicc. andconcentrated in vacuo; a residue of 1.6 g remains (product B).

[0592] Product B:

[0593] Y: 32.6% (1.6 g), C₂₁H₁₉ClN₂O₄S, MW=430.91;

[0594] Mp: dec 140° C.;

[0595] IR (NaCl): 1/λ (cm⁻¹)=3022, 2951, 2886, 1708, 1596, 1545, 1488,1459, 1399, 1220, 1121, 1098, 833;

[0596]¹H-NMR (CD₃OD): δ (ppm)=7.29-7.17 (AA′+AA′, 4H, arom), 7.14-7.10(BB′, 2H1, arom), 6.94-6.89 (BB′, 2H, arom), 4.39 (t, 2H, CH₂), 3.63 (s,3H, COOCH₃), 3.00 (t, 2H, CH₂), 2.56 (quin, 2H, CH₂).

[0597] Product A:

[0598] is identical with product from Example 24

EXAMPLE 24

[0599]4-[1-(4-Chlorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0600] a) tert-Butyl1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate

[0601] 7-(4-Chlorophenyl)-6-phenyl-2,3-dihydro-1H-pyrrolizine (Example21 b, 0.75 g, 2.5 mmol), dissolved in THF (10 ml), is treated withtriethylamine (0.3 ml, 0.25 g, 2.5 mmol). A solution of diphosgene (0.25g, 1.25 mmol), dissolved in THF (5 ml), is added dropwise to thissolution at RT, and it is stirred for 18 h. tert-Butyl alcohol (abs.,1.0 ml, 0.786 g, 10 mmol) and triethylamine (0.7 ml, 0.51 g, 5 mmol) arethen added, and the mixture is stirred at RT for a further 48 h. Thereaction mixture is partitioned between water (30 ml) and CHCl₃ (60 ml),and the ether phase is washed with Na₂CO₃ solution (5%, 20 ml). Afterremoval of the solvent in vacuo, an oily residue (0.7 g), which by TLC(SiO₂, hexane/CH₂Cl₂ 1:1) still contains starting material (Rf 0.75) inaddition to product (Rf 0.3), is obtained from the THF/CHCl₃ phase driedusing Na₂SO₄ sicc. The residue is purified by CC (SiO₂, hexane/CH₂Cl₂1:1); 190 mg of the pure ester are obtained.

[0602] Y: 20% (0.19 g), C₂₄H₂₄ClNO₂, MW=393.92;

[0603]¹H-NMR (CDCl₃): δ (ppm)=7.27-7.13 (m, 5H, arom), 7.12-6.89 (qu,4H, arom), 4.42-4.35 (t, 2H, CH₂), 3.02-2.94 (t, 2H, CH₂), 2.57-2.49(qui, 2H, CH₂).

[0604] b)4-[1-(4-Chlorophenyl)-6,7-dihydro-5H-pyrrolizin-2-yl]benzenesulphonamide

[0605] tert-Butyl1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate(190 mg, 0.5 mmol) is taken up in CHCl₃ (10 ml), the solution is cooledto 0-5° C. in an ice bath, and a solution of chlorosulphonic acid (1 ml,1.75 g, 15 mmol) in CHCl₃ (20 ml) is then slowly added dropwise (IT<10°C., 15 min). The mixture is then stirred at RT for 12 h, a solution ofNH₃ in dichloroethane (40 ml) saturated in the cold is added and it isstirred at RT for a further 12 h. It is then treated with ice water (5ml), and the phase mixture is sucked through a G3 frit. The CHCl₃ phaseis separated from the now clear aqueous phase in a separating funnel.The filter residue is washed with a little water and CHCl₃ and dried invacuo. The dried solid substance is crystallized from MeOH: 0.13 g(70%).

[0606] Y: 70% (130 mg), C₁₉H₁₇ClN₂O₂S, MW=372.88;

[0607] IR (NaCl): 1/λ (cm⁻¹)=3432, 3178, 3055, 1596, 1547, 1489, 1445,1426, 1384, 1288, 1185, 1091, 1042, 833, 731, 721, 637;

[0608]¹H-NMR (DMSO-d₆): δ (ppm)=7.24-717 (AA′+AA′+CH, 5H, arom),7.09-6.89 (BB′+BB′, 4H, arom), 4.87 (s, 2H, SO₂NH₂), 4.29 (t, 2H, CH₂),2.96 (t, 2H, CH₂), 2.52 (quin, 2H, CH₂).

[0609] The compounds of Examples 25-29 are prepared according toanalogous procedures:

[0610] spectroscopic data for compounds 25-29 are listed in the figures.

EXAMPLE 30

[0611] 4-(3-Methyl-6.7-dihydro-5H-pyrrolizin-1-yl)benzenesulphonamide

[0612] a) 7-Phenyl-2,3-dihydro-1H-pyrrolizine

[0613] 2-Benzyl-1-pyrroline (Example 1b, 85%, 74 g, 0.395 mol),dissolved in MeOH (360 ml), is treated with NaHCO₃ (38 g, 0.45 mol), andthe mixture is cooled to 5° C. A solution of chloroacetaldehyde (45%strength in water, 68 g, 0.4 mol), dissolved in MeOH (100 ml) is addeddropwise to the solution at this temperature, and the mixture is stirredfor 18 h with exclusion of light.

[0614] The reaction mixture with the substance at the bottom ispartitioned between semi-saturated NaCl solution (900 ml) and ethylacetate (900 ml), the ethyl acetate phase is washed with saturated NaClsolution (300 ml) and dried using Na₂SO₄ sicc., and the solvent isremoved in vacuo. The residue (82 g) has the purity necessary for thefurther reactions (TLC SiO₂, hexane/diethyl ether 1:1, Rf 0.65).

[0615] Y: 112% (82 g), C₁₃H₁₃N, MW=183.26;

[0616] Mp: 60.4AC;

[0617] IR (NaCl): 1/λ (cm⁻¹)=2360, 1601, 1551, 1498, 1440, 1295, 1245,1072, 958, 903, 764, 711, 690, 654, 609;

[0618]¹H-NMR (CDCl₃): δ (ppm)=7.50-7.07 (m, 5H, arom), 6.64 and 6.53(2×CH), 4.00 (t, 2H, CH₂), 3.09 (t, 2H, CH₂), 2.62-2.52 (q, 2H, CH₂);

[0619]¹³C-NMR (CDCl₃): δ (ppm)=136.6, 134.2, 128.4, 124.9, 124.3, 115.0,114.3, 110.0, 46.1, 27.8, 25.2.

[0620] b) Ethyl oxo-(1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)acetate

[0621] 7-Phenyl-2,3-dihydro-1H-pyrrolizine (crude, 82 g, about 0.4 mol)is dissolved in THF (400 ml), the solution is cooled to 0-5° C. in anice bath, then a solution of ethyl oxalyl chloride (50 ml, 61.1 g, 0.448mol) in THF (200 ml) is added dropwise in the course of 30 min (IT<10°C., 15 min). The mixture is then stirred at this temperature for afurther 1 h and at RT for 1 h. It is then treated with Na₂CO₃ solution(saturated, 300 ml) with ice-cooling and extracted 3 times with ethylacetate (300 ml). The organic phase is washed in a separating funnelwith NaCl solution (saturated, 300 ml) and separated from the aqueousphase. The ethyl acetate-THF phase is dried using Na₂SO₄ sicc., and thesolvent is evaporated in vacuo. The dried residue (99 g) in CH₂Cl₂ ispurified by CC (SiO₂, ether): 46.4 g of pure substance: (41.1%).

[0622] Y over a and b: 41% (46.4 g), C₁₇H₁₇NO₃, MW=283.33;

[0623] Mp: 101.8° C.;

[0624] IR (NaCl): 1/λ (cm⁻¹)=1734, 1630, 1450, 1428, 1217, 1148, 1046,1006, 763, 696

[0625]¹H-NMR (DMSO-d₆): δ (ppm)=7.63 (s, 1H, CH), 7.51-7.22 (m, 5H,arom), 4.46-4.35 (t, 2H, CH₃ and q, 2H, CH₂), 3.11 (t, 2H, CH₂), 2.62(quin, 2H, CH₂), 1.43 (t, 3H, CH₃).

[0626] GC-MS: m/z (rel. int. [%]=284 (06); 283 (M^(+), 30); 211 (20);210 ((M-COOEt^())⁺; 100); 167 (05); 154 (05); 153 (05); 141 (06); 127(05); 115 (05).

[0627] c) 1-Phenyl-6.7-dihydro-5H-pyrrolizin-3-yl acetic Acid

[0628] Ethyl oxo-(1-phenyl-6,7-dihydro-5H-pyrrolizin-3-yl) acetate (46g, 0.163 mol) is dissolved in diethylene glycol-THF (1:1, 750 ml),hydrazine hydrate (80% strength, 110 ml, 113 g, 1.8 mol) is added, themixture is adjusted to a temperature of 60° C. in an oil bath, and themixture is stirred at this temperature for 1.5 h. THF is distilled off(350 ml) and the bottom temperature is increased to 100° C. stepwise (60min). The mixture is allowed to cool to 60° C., KOH platelets (85%, 173g, 2.62 mol) are added to the mixture, the mixture temperature isincreased to 120° C., and it is subsequently stirred at this temperaturefor a further 2 h and then cooled. When 50° C. is reached, it is treatedwith ice water (1.2 1) and extracted 3 times with ethyl acetate (900ml). The aqueous phase is acidified to pH 3 using HCl (20% strength),extracted 3 times with ethyl acetate (900 ml) and the organic phase iswashed in a separating funnel with NaCl solution (saturated, 300 ml).The ethyl acetate phase is dried using Na₂SO₄ sicc., and the solvent isevaporated in vacuo. The residue crystallizes from hexane-ether 1:1:10.7g (27.2%). After concentrating the mother liquor and taking up theresidue in ethyl acetate, the solution is washed with water, dried overNa₂SO₄ sicc. and concentrated again: a further 11.3 g of product remain.

[0629] Y: 56% (22 g), C₁₅H₁₅NO₂, MW=241.29;

[0630] Mp: 108.8° C.;

[0631] IR (NaCl): 1/λ (cm⁻¹)=2891, 1708, 1604, 1419, 1398, 1296, 1235,758, 696;

[0632]¹H-NMR (DMSO-d₆): δ (ppm)=7.46-7.09 (m, 5H, arom), 6.40 (s, 1H,CH), 3.96-3.89 (t, 2H, CH₂), 3.11-3.04 (t, 2H, CH₂), 2.60-2.56 (q, 2H,CH₂);

[0633]¹³C-NMR (DMSO-d₆): δ (ppm)=171.9, 136.6, 133.1, 128.6, 124.1,123.9, 120.9, 113.5, 108.6, 44.1, 32.4, 27.1, 25.4.

[0634] c) 5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0635] 1-Phenyl-6,7-dihydro-5H-pyrrolizin-3-yl)acetic acid (21 g, 0.087mol) is filled into a flask under protective gas, and this flask isimmersed in an oil bath maintained at a temperature of 180° C. Themixture is treated at 180° C. until the evolution of gas subsides (45min) and a TLC sample (SiO₂, ether-hexane 1:1) indicates completeconversion. The cooled melt is dissolved in ethyl acetate (300 ml) inthe presence of heat, and washed 3 times with Na₂CO₃ solution (10%, 100ml), once with NaCl (50 ml) and once with water (50 ml). The ethylacetate phase is dried over Na₂SO₄ sicc. and concentrated: 16.1 g ofyellow-brown solid (93.8%) remain.

[0636] Y: 93.8% (16.1 g), C₁₄H₁₅N, MW=197.28;

[0637] Mp: 58.9° C.;

[0638] IR (NaCl): 1/λ (cm⁻¹)=2919, 2887, 1601, 1521, 1418, 1405, 1300,1211, 1066, 750, 691, 653, 503;

[0639]¹H-NMR (CDCl₃): δ (ppm)=7.45-7.08 (m, 5H, arom), 6.20 (1H, CH),3.87-3.80 (t, 2H, CH₂), 3.10-3.03 (t, 2H, CH₂), 2.58-2.51 (t, 2H, CH₂),2.23 (s, 3H, CH₃);

[0640]¹³C-NMR (CDCl₃): δ (ppm)=136.8, 132.2, 128.4, 124.9, 124.1, 123.9,114.4, 107.1, 44.1, 27.7, 25.7, 11.9.

[0641] d) 4-(3-Methyl-6,7-dihydro-5H-pyrrolizin-1-yl)benzenesulphonamide

[0642] 5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (370 mg, 1.9 mmol)is suspended in chlorosulphonic acid (1.5 ml, 2.62 g, 22.5 mmol), whichhas been cooled to −101C, with exclusion of moisture. The mixture issubsequently stirred at RT for 72 h, then treated cautiously with ice(10 g), extracted with chloroform (3×20 ml), and the combined chloroformextracts are washed with cold NaCl solution. The washed CHCl₃ extract isdried over Na₂SO₄ sicc.; then NH₃ from a pressurized container is passedinto the filtered CHCl₃ solution of the sulphochloride. The suspensionsaturated with NH₃ is stirred for a further 1 h, then treated with icewater (15 ml) and the phase mixture is filtered off with suction througha G3 frit. The CHCl₃ phase is separated in a separating funnel from thenow clear aqueous phase, the latter is extracted a further two timeswith CHCl₃ (150 ml), and the CHCl₃ phases are combined, dried overNa₂SO₄ sicc. and concentrated in vacuo. The solid substance (270 mg,53%) remaining after stripping off the solvent is crystallized from EtOH60%: 75 mg (14.2%).

[0643] Y: 53% (270 mg), C₁₄H₁₆N₂O₂S, MW=276.36;

[0644] Mp: 198-207° C.;

[0645] IR (NaCl): 1/λ (cm⁻¹)=3348, 3253, 1596, 1528, 1430, 1327, 1302,1151, 1095, 836, 543, 412;

[0646]¹H-NMR (CDCl₃): δ (ppm)=7.72-7.49 (AA′BB′, 4H, arom), 7.20 (NH₂),6.23 (s, 11H, CH), 3.84 (t, 2H, CH₂), 3.03 (t, 2H, CH₂), 2.49 (quin, 2H,CH₂), 2.17 (s, 3H, CH₃);

[0647]¹³C-NMR (CDCl₃): δ (ppm)=134, 127.1, 126.5, 126.1, 125, 124.2,113, 107.1, 44.0, 27.3, 25.8, 11.6.

[0648] The compound of Example 33 is synthesized from2-benzyl-1-pyrroline (Example 1b) and α-bromo-tert-butyl methyl ketoneaccording to the reaction sequence described for Example 30; theintroduction of the 5-methyl group takes place via conversion of the6-tert-butyl-7-phenyl-2,3-dihydro-1H-pyrrolizine into the ethyl5-oxoacetate and its reduction to the acetic acid, which decarboxylatesat elevated temperature.

[0649] The compounds of Examples 31 and 32 are prepared from2-benzyl-1-pyrroline (Example 1b) and the haloketones 2-chlorobutanone(Example 31), or 2-chlorocyclohexanone (Example 32) analogously to thereaction sequence of method A of Example 34 described below. Thesubstituents in positions 5 and 6 are introduced via an appropriatebromoketone (R2—CO—CHBr—R3).

EXAMPLE 34

[0650]4-(3-Trifluoromethyl-6,7-dihydro-5H-pyrrolizin-1-yl)benzenesulphonamide

[0651] a) 5-Trifluoromethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0652] Method A:

[0653] 2-Benzyl-1-pyrroline (Example 1b, 85%, 4.4 g, 24 mmol) and1-bromo-3,3,3-trifluoroacetone (3.82 g, 20 mmol) are mixed with oneanother in a 25 ml flask (exothermic), and the mixture is then stirredat 80° C. for 4 h. Two isomeric products are formed in the ratio 0.8:1(TLC: SiO₂— hexane/ether 8:2, Rf 0.6+Rf 0.3). The mixture is treatedwith water (10 ml) and acidified with HCl (10%, 5 ml); it is extracted 3times with ethyl acetate (100 ml). The ethyl acetate phase is dried overNa₂SO₄ sicc. and concentrated. The residue (2.0 g) is purified by CC(SiO₂, n-hexane/ether 8:2):

[0654] TY: 1.28 g (25%).

[0655] Method B:

[0656] 2-Benzyl-1-pyrroline (Example 1 b, 85%, 6.3 g, 34 mmol),dissolved in methanol (60 ml), 1-bromo-3,3,3-trifluoroacetone (3.82 g,20 mmol) and NaHCO₃ (1.85 g, 22 mmol) are mixed with one another in a100 ml flask, and the mixture is then stirred at RT for 88 h. Twoisomeric products are formed in the ratio 2:1 (TLC: SiO₂— hexane/ether8:2, Rf 0.6+Rf 0.3). The mixture is treated with water (50 ml) andacidified (pH 3-4) with HCl (10%); it is extracted 3 times with diethylether (150 ml). The ether phase is dried over Na₂SO₄ sicc. andconcentrated. The residue (7.1 g) is purified by CC (SiO₂,n-hexane/ether 8:2):

[0657] TY: 3.05 g (54%).

[0658] Fractions1-16:6-Trifluoromethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine;

[0659] Y: 36% (2.0 g), C₁₄H₁₂F₃N, MW=251.25;

[0660] Mp: 67.8° C.;

[0661] IR (NaCl): 1/λ (cm⁻¹)=3446, 2922, 2362, 1603, 1565, 1484, 1450,1375, 1266, 1208, 1143, 1098, 758, 690;

[0662]¹H-NMR (CDCl₃): δ (ppm)=7.38-7.08 (5H, arom), 6.78 (s, 1H, CH),4.02-3.95 (t, 2H, CH₂), 3.02-2.95 (t, 2H, CH₂), 2.59-2.48 (q, 2H, CH₂);

[0663]¹³C-NMR (CDCl₃): δ (ppm)=137, 135.2, 128.7, 125.3, 125.2, 124.2,119, 115.6, 111.8, 46.0, 27.4, 25.2.

[0664] Fraction 18-24: Mixed Fraction.

[0665] Fraction26-56:5-Trifluoromethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine, 520 mg;

[0666] Y: 18% (1.0 g), C₁₄H₁₂F₃N, MW=251.25;

[0667] Mp: 61.60° C.;

[0668] IR (NaCl): 1/λ (cm⁻¹)=2906, 2360, 1605, 1531, 1458, 1298, 1196,1138, 1109, 1084, 971, 778, 765, 702;

[0669]¹H-NMR (CDCl₃): δ (ppm)=7.44-7.23 (5H, arom), 7.00 (s, 1H, CH),4.03-3.96 (t, 2H, CH₂), 2.96-2.88 (t, 2H, CH₂), 2.55-2.48 (q, 2H, CH₂);

[0670]¹³C-NMR (CDCl₃): δ (ppm)=136.8, 134.6, 132.0, 128.3, 128.2, 126.6,126.0, 121.3, 115, 46.7, 27.5, 24.3.

[0671] b)4-(3-Trifluoromethyl-6,7-dihydro-5H-pyrrolizin-1-yl)benzenesulphonamide

[0672] 5-Trifluoromethyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (750 mg, 3mmol) is suspended in chlorosulphonic acid (10 ml, 17.5 g, 150 mmol)with exclusion of moisture. The mixture is then stirred at RT for 16 h.It is cautiously treated with ice (10 g) with ice-cooling, extractedwith chloroform (3×30 ml) and the combined chloroform extracts arewashed with cold NaCl solution. The washed CHCl₃ extract is dried overNa₂SO₄ sicc., and the filtered CHCl₃ solution of the sulphochloride isthen cooled to 5° C. NH₃ is passed in from a pressurized container for 1h. The NH₃-saturated suspension is stirred for a further 2 h and thentreated with ice water (15 ml). The CHCl₃ phase is separated in aseparating funnel from the aqueous phase, the latter is extracted afurther two times with CHCl₃ (150 ml), and the CHCl₃ phases arecombined, washed with water (20 ml), dried over Na₂SO₄ sicc. andconcentrated in vacuo. The solid substance remaining after stripping offthe solvent (0.5 g, 50%, concentration 90%) is crystallized from ethylacetate: 0.2 g (concentration 98%).

[0673] Y: 45% (0.5 g, 90% strength), C₁₄H₁₃F₃N₂O₂S, MW=330.33;

[0674] Mp: 153.5° C.;

[0675] IR (NaCl): 1/λ (cm⁻¹) 3388, 3282, 1594, 1536, 1296, 1198, 1149,1112, 1091, 1079, 796, 598;

[0676]¹H-NMR (CDCl₃): δ (ppm)=7.95-7.44 (AA′BB′+br, 6H, arom +NH₂), 7.04(s, 1H, CH), 4.03 (t, 2H, CH₂), 2.95 (t, 2H, CH₂), 2.57 (quin, 2H, CH₂);

[0677]¹³C-NMR (CDCl₃): δ (ppm)=142.9, 135.5, 131.8, 128.7, 128.3, 126.1,125.6, 123.5, 115.3, 46.7, 27.3, 24.1.

EXAMPLE 35

[0678]4-(2-Isobutyl-3-methyl-6,7-dihydro-51H-pyrrolizin-1-yl)benzenesulphonamide

[0679] a)2-Methyl-1-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)propan-1-one

[0680] 5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 30 c, 7.8g, 0.039 mol), dissolved in dichloroethane (140 ml) is treated at RTwith isobutyryl chloride (4.6 ml, 4.8 g, 0.043 mol), and tintetrachloride (5.3 ml, 11.8 g, 0.045 mol) in dichloroethane (30 ml) issubsequently added dropwise.

[0681] The mixture warms to 35° C. and is refluxed for 2 h at 73° C. Itis then poured onto ice, rendered alkaline with NaOH (10%, 200 ml) andthe organic phase is separated in a separating funnel. The alkali phaseis extracted a further two times with dichloromethane (400 ml), which isadded to the dichloroethane phase. This extract is dried over Na₂SO₄sicc. and evaporated to dryness in vacuo. The residue (11.3 g) is washedwith a little diisopropyl ether and the crystals (7.56 g, 72.5%) arefiltered off with suction and dried.

[0682] Y: 72.5% (7.56 g), C₁₈H₂₁NO, MW=267.37;

[0683] Mp: 158.7° C.;

[0684] IR (NaCl): 1/λ (cm⁻¹)=2958, 1648, 1599, 1518, 1421, 1407, 1115,977, 702;

[0685]¹H-NMR (CDCl₃): δ (ppm)=7.35-7.22 (m, 5H, arom), 3.91 (t, 2H,CH₂), 2.84 (t, 2H, CH₂), 2.70 (sept., 1H, CH(CH₃)₂), 2.52-2.40 (quin,2H, CH₂), 2.39 (s, 3H, CH₃), 0.925 (d, 6H, CH(C _(H) ₃)₂);

[0686]¹³C-NMR (CDCl₃): δ (ppm)=205.2, 136.8, 133.3, 130.0, 128.9, 128.1,125.8, 123.0, 116.0, 44.5, 38.1, 26.9, 23.8, 19.1, 12.1.

[0687] b) 6-Isobutyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0688] A solution of2-methyl-1-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-propan-1-one(7.5 g, 28 mmol) in CH₂Cl₂ (140 ml) is treated successively with NaCNBH₃(7.4 g, 112 mmol) and ZnI₂ (12.5 g, 40 mmol) and the mixture is stirredat RT for 2 h (TLC: SiO₂/diethyl ether; starting material Rf 0.75;product Rf 8.8). The mixture is covered with a layer of H3PO4 (8%, 200ml) with ice cooling and stirred for 16 h. The CH₂Cl₂ phase is separatedand washed with water (50 ml), dried over Na₂SO₄ sicc. and concentratedin vacuo. The residue (7.5 g, 106%) is recrystallized from MeOH.

[0689] Y: 64.4% (4.5 g), C₁₈H₂₃N, MW=253.39;

[0690] Mp: 95.4° C.;

[0691] IR(NaCl): 1/λ (cm⁻¹)=2916, 2861, 1599, 1527, 1453, 1421, 1305,760, 698;

[0692]¹H-NMR (CDCl₃): δ (ppm)=7.35-7.23 (m, 5H, arom), 3.87 (t, 2H,CH₂), 2.94 (t, 2H, CH₂), 2.52-2.41 (quin +d, 4H, CH₂+CH₂CH), 2.17 (s,3H, CH₃), 1.62 (m., 1H, CH₂CH(CH₃)₂), 0.795 (d, 6H, CH(CH ₃)₂);

[0693]³C-NMR (CDCl₃): δ (ppm)=137.9, 132.0, 128.1, 128.1, 124.5, 120.4,120.4, 114.7, 44.4, 34.5, 30.3, 27.0, 24.7, 22.6, 10.4.

[0694] c)4-(2-Isobutyl-3-methyl-6,7-dihydro-5H:-pyrrolizin-1-yl)benzenesulphonamide

[0695] 6-Isobutyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (4.0 g,16 mmol) is dissolved in CHCl₃ abs. (20 ml), the solution is cooled to5° C. and chlorosulphonic acid (10 ml, 17.5 g, 150 mmol) is slowly addeddropwise. The mixture is heated for 2.5 h (5 8-61° C.) (TLC: SiO₂,ether-hexane 1:1, starting material Rf 0.9, chlorosulphonic acid Rf0.8). The reaction mixture is quenched on ice (100 ml) and taken up inCHCl₃ (120 ml). The ice-water phase is extracted 3 times with CHCl₃ (120ml), and the collected CHCl₃ solution is washed (100 ml of saturatedNaCl solution), dried (Na₂SO₄ sicc.) and concentrated (residue: 7.2 g).The chlorosulphonation product (7.2 g) is dissolved in THF abs., andconcentrated NH₄OH (25% strength, 4 ml) is slowly added dropwise. Themixture is stirred at RT for 16 h, treated with semi-concentrated NaClsolution (60 ml) and extracted 3 times with ethyl acetate (150 ml). Thewashed (40 ml of saturated NaCl solution) ethyl acetate phase is dried(Na₂SO₄ sicc.) and concentrated. The residue (5.0 g, concentration 83%according to HPLC) is digested with ether (10 ml) at RT (2.76 g, 51%,concentration 94%) and subsequently crystallized from ethanol (20 ml)and dried:

[0696] Y: 34,4%, (1.83 g, 99.7% strength), C₁₈H₂₄N₂O₂S, MW=332.47;

[0697] Mp: 197.1° C.;

[0698] IR (NaCl): 1/λ (cm⁻¹)=3337, 3235, 2948, 1595, 1332, 1161, 1093,546;

[0699]¹H-NMR (DMSO-d₆): δ (ppm)=7.74-7.42 (m, 5H, arom), 7.24 (NH₂),3.83 (t, 2H, CH₂), 2.87 (t, 2H, CH₂), 2.41-2.37 (quin +d, 4H,CH₂+CH₂CH), 2.09 (s, 3H, CH₃), 1.62 (m., 1H, CH₂CH(CH₃)₂), 0.735 (d, 6H,CH(CH ₃)₂);

[0700]¹³C-NMR(DMSO-d₆): δ (ppm)=141.7, 139.3, 133.1, 126.8, 125.8,120.7, 119.1, 112.4, 44.2, 40.2, 34.3, 29.6, 26.5, 24.7, 22.4, 10.1.

[0701] The compounds of Examples 36-38 are prepared according toanalogous procedures:

[0702] spectroscopic data for compounds 36-38 are listed in the figures.

EXAMPLE 39

[0703]4-[2-(Perfluoroisopropyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzenesulphonamide

[0704] a)2,2,2-Trifluoro-1-(3-methyl-1-phenol-6,7-dihydro-5H-pyrrolizin-2-yl)ethan-1-one

[0705] 5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 30 c, 90%,2.2 g, 0.01 mol), dissolved in dichloromethane (30 ml), is treated at RTwith trifluoroacetic anhydride (1.4 ml, 2.14 g, 0.01 mol) and zincchloride (1.36 g, 0.01 mol). The mixture is stirred at RT for 2 h, afterwhich a TLC sample (SiO₂, hexane-ether 1:1, starting material Rf 0.8,main product Rf 0.4, by-product Rf 0.6) indicates complete reaction. Themixture is then treated with water, rendered alkaline with NaOH (10%,200 ml) and extracted a further 2 times with CH₂Cl₂ (50 ml). Thecollected organic phases are combined, dried over Na₂SO₄ sicc. andevaporated to dryness in vacuo.

[0706] The residue is purified by means of CC (SiO₂, 200 g, hexane-ether1:1): first 0.34 g of the by-product fraction, then 1.3 g (44.4% yield)of the desired compound are obtained.

[0707] Y: 44.4% (13 g); C₁₆H₁₄F₃NO, MW=293.29;

[0708] Mp.: 111.4° C.,

[0709] IR (NaCl): 1/λ (cm⁻¹)=1662, 1601, 1446, 1423, 1383, 1236, 1194,1124, 1080, 974, 759, 706, 698;

[0710]¹H-NMR (CDCl₃): δ (ppm)=7.37-7.21 (m, 5H, arom), 3.95 (t, 2H,CH₂), 2.84 (t, 2H, CH₂), 2.52 (quin, 2H, CH₂), 2.45 (s, 3H, CH₃);

[0711] GC-MS (70 eV): m/z (rel. int. [%]=293 (59); 224 (100); 207 (20);225 (17); 294 (10); 127 (08); 167 (06); 194 (05).

[0712] b)1,1,1,3,3,3-Hexafluoro-2-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-propan-2-ol

[0713] The solution of2,2,2-trifluoro-1-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-ethan-1-one(1.8 g, 6 mmol) in THF (70 ml) is treated successively withtrifluoromethyltrimethylsilane (7.5 ml, 2 M in THF, 15 mmol) andtetrabutylammonium fluoride (bound to silica gel, 1.1 mmol/g of SiO₂;0.5 g, 0.55 mmol) and stirred at 40° C. for 2 h (TLC:SiO₂/hexane-diethyl ether 1:1; starting material Rf 0.4; product Rf8.5). The mixture is cooled in an ice bath and treated with NaOH (70 ml,10% strength solution; 7 g, 175 mmol) and stirred at room temperaturefor 1 h. The THF phase is treated with diethyl ether (50 ml) andseparated in a separating funnel and the aqueous phase is againextracted with diethyl ether (50 ml). The combined organic phases arewashed with water (50 ml), dried over Na₂SO₄ sicc. and concentrated invacuo.

[0714] Y: 110% (2.4 g); C₁₈H₂₃N, MW=253.39;

[0715] Mp.: 106.1° C.

[0716] IR (NaCl): 1/λ (cm⁻¹)=3522, 2958, 2924, 1603, 1423, 1303, 1263,1223, 1203, 1132, 962, 948, 728, 710;

[0717]¹H-NMR (CDCl₃): δ (ppm)=7.35-7.25 (m, 5H, arom), 3.94 (t, 2H,CH₂), 3.57 (s, 1H, OH), 2.67 (t, 2H, CH₂), 2.45 (quin +d, 4H, CH₂+CH₂CH), 2.29 (s, 3H, CH₃);

[0718] GC-MS (EI-70 eV) m/z (rel. int. [%]=363 (97); 97 (100); 294 (98);196 (24); 364 (19); 295 (18); 198 (17); 182 (13); 224 (12); 362 (06);276 (06); 112 (06); 128 (05); 127 (05).

[0719] c)5-Methyl-6-perfluoroisopropyl-7-phenyl-2,3-dihydro-1H-pyrrolizine

[0720] The solution of1,1,1,3,3,3-hexafluoro-2-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)propan-2-ol(2.2 g, 6 mmol) in CH₂Cl₂ abs. (25 ml) is slowly added dropwise at −50°C. to a solution of diethylaminosulphur trifluoride (DAST, 1.5 ml, 1.845g, 11.5 mmol) in 25 ml of CH₂Cl₂ abs. The cooling bath is removed andthe mixture is allowed to come to room temperature in the course of 2 hwith stirring (TLC: SiO₂/hexane-diethyl ether 1:1; starting material Rf0.4; product Rf 8.5). The mixture is cooled in an ice bath and renderedalkaline with NaHCO₃ solution (30 ml) and stirred for 10 min. The CH₂Cl₂phase is separated in a separating funnel and the aqueous phase is againextracted with diethyl ether (50 ml). The combined organic phases arewashed with satd. sodium chloride solution (50 ml), dried over Na₂SO₄sicc. and concentrated in vacuo. The residue is purified by CC:SiO₂/hexane-diethyl ether 2:1; starting material Rf 0.3; product Rf0.5).

[0721] Y: 69.9% (1.53 g); C₁₇H₁₄F₇N, MW=365.30;

[0722] Mp: 63.10° C.

[0723] IR (NaCl): 1/λ (cm⁻¹)=2964, 2360, 1606, 1423, 1304, 1275, 1234,1217, 1134, 966, 729, 706;

[0724]¹H-NMR (CDCl₃): δ (ppm)=7.3-7.19 (m, 5H, arom), 3.93 (t, 2H, CH₂),2.68 (t, 2H, CH₂), 2.46 (quin+d, 4H, CH₂+CH ₃CH), 2.29 (s, 3H, CH₃);

[0725] GC-MS (EI-70 eV) m/z (rel. int. [%]=365 (100); 296 (57); 276(26); 366 (19); 364 (15); 297 (11); 100(09); 268 (08); 212 (08); 196(08); 207 (07); 199 (07); 294 (06); 227 (06); 226 (06); 277 (05); 114(05).

[0726] d)4-(5-Methyl-6-perfluoroisopropyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-1-yl)benzenesulphonamide

[0727] 5-Methyl-6-perfluoroisopropyl-7-phenyl-2,3-dihydro-1H-pyrrolizine(0.7 g, 1.9 mmol) is introduced into chlorosulphonic acid (2.6 ml, 4.54g, 39 mmol) at −30° C. The mixture is warmed to 0-10° C. during thecourse of 2.5 h and then stirred for 42 h at RT until conversion intothe acid chloride is complete. The monitoring of the reaction is carriedout by means of HPLC. After this time, about 75% of the substanceemployed is present as sulphochloride in addition to 5% sulphonic acidand about 4% of starting material (TLC: SiO₂, ether-hexane 1:1, startingmaterial Rf 0.7, sulphonic acid Rf 0, chlorosulphonic acid Rf 0.4). Thereaction mixture is quenched on ice water (20 ml) and the ice-waterphase is extracted 3 times with CHCl₃ (3×40 ml). The collected CHCl₃extracts are washed (100 ml of satd. NaCl solution), dried (Na₂SO₄sicc.) and concentrated (residue: 0.94 g, 94%, concentration accordingto HPLC: 88%). The chlorosulphonation product is dissolved in THF abs.(30 ml) and conc. NH₄OH (25% strength, 3 ml) is added with ice-cooling.The mixture is stirred at RT for 1 h, treated with semi-concentratedNaCl solution (60 ml) and extracted 3 times with ethyl acetate (3×50ml). The ethyl acetate phase is dried (Na₂SO₄ sicc.) and concentrated.The residue (0.91 g, concentration 83.5% according to HfPLC, 90% yield)is first crystallized from aqueous EtOH (50% G/G; 6 ml) (concentrationaccording to HPLC: 89.5%) and then crystallized from absolute ethanol (4ml) and dried: (0.25 g, concentration according to HPLC: 96.8%). Afurther 0.15 g was obtained from the mother liquor (96% according toHPLC).

[0728] Y: 47.4%, (0.4 g), C₁₇H₁₅F₇N₂O₂S, MW=444.37;

[0729] Mp: 199.60° C.

[0730] IR (NaCl): 1/λ (cm⁻¹)=3340, 3253, 1598, 1338, 1276, 1221, 1162,1145, 1132, 1092, 982, 968, 841, 739, 729, 551;

[0731]¹H-NMR (DMSO-d₆): δ (ppm)=7.85 and 7.37 (AA′BB′, arom, 4H,J=8.4),4.85 (NH₂), 3.95 (t, 2H, CH₂, J=7.0), 2.68 (t, 2H, CH₂, J=7.0), 2.49(quin, 2H, CH₂, J=7.0), 2.29 (s, 3H, CH₃);

[0732] GC-MS (El, 70 eV): m/z (rel int. %)=444 (100); 226 (52); 295(50); 445 (21); 345 (11); 443 (09); 296 (09); 227 (09); 446 (07); 275(07); 225 (07); 364 (06); 294 (05)

EXAMPLE 40

[0733]4-[2-(1,1,1,2,2,3,3-Heptafluoro-4-butyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzene-sulphonamide

[0734] a)1,1,1,2,2,3,3-Heptafluoro-4-(3-methyl-1-phenyl-6,7-dihydro-5H1-pyrrolizin-2-yl)butan-4-one

[0735] 5-Methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (Example 30 c, 1.0g, 0.005 mol), dissolved in dichloroethane (20 ml) is treated withheptafluorobutyryl chloride (0.83 ml, 1.3 g, 0.0055 mol) at RT andfinally tin tetrachloride (0.7 ml, 1,56 g, 0.006 mol) in dichloroethane(5 ml) is added dropwise. The mixture warms to 35° C. and is stirred atRT for 16 h. The GC-MS analysis shows a 60% reaction. The reactionmixture is rendered alkaline with NaOH (25%, 25 ml) in an ice bath and,after addition of CH₂Cl₂ (25 ml), the organic phase is separated in aseparating funnel. The alkali phase is extracted a further two timeswith dichloromethane (2×20 ml). These CH₂Cl₂ extracts are combined,dried over Na₂SO₄ sicc. and evaporated to dryness in vacuo.

[0736] The residue (1.4 g) is purified by CC (SiO₂ (120 g),hexane-diethyl ether 7:3): 0.46 g of starting material are recovered inthe forerun. In a second separation process, 0.180 g are obtained froman intermediate fraction and, in the afterrun of the first separation,0.62 g of product, together 0.8 g (40.7% of theory).

[0737] Y: 40.7% (0.8 g); C₁₈H₁₄F₇NO, MW=393.31;

[0738] Mp: 77.0° C.,

[0739] IR (NaCl): 1/λ (cm⁻¹)=1667, 1505, 1422, 1384, 1343, 1239, 1213,1175, 1117, 1093, 870, 764, 717, 703;

[0740]¹H-NMR (CDCl₃): δ (ppm)=7.37 (m, 5H, arom), 3.95 (t, 2H, CH₂),2.89 (t, 2H, CH₂), 2.53 (quin, 2H, CH₂), 2.39 (s, 3H, CH₃);

[0741] GC-MS (El, 70 eV): m/z (rel. int. %)=224.1 (100); 393.1 (35);225.1 (18); 394.1 (07); 127.0 (06).

[0742] b)2-(1,1,1,2,2,3,3-Heptafluoro-4-butyl)-3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizine

[0743] The solution of1,1,1,2,2,3,3-heptafluoro-4-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-butan-4-one(0.62 g, 1.6 mmol) in dichloroethane (20 ml) is treated successivelywith NaCNBH₃ (0.42 g, 6.4 mmol) and ZnI₂ (0.71 g, 2.24 mmol) andrefluxed for 4 days (d). After 2 days, NaCNBH₃ (0.42 g, 6.4 mmol) andZnI₂ (0.71 g, 2.24 mmol) are again added. The reaction is observed bymeans of GC-MS. After 2 days, 40% of the compound employed is reacted,and after 4 days 89%, in addition to a further 11% of starting material.The reaction is then terminated by addition of dilute phoshoric acid(8%, 50 ml). After the evolution of gas has ended, the mixture isextracted with methylene chloride, the organic phase is washed withwater (50 ml) and the solvent is stripped off in vacuo after drying overNa₂SO₄ sicc. The residue (0.65 g, 82.4%, 77% strength according toGC-MS(TIC)) is employed in the subsequent reaction without furtherpurification.

[0744] Y: 82.4% (0.65 g, 77% according to GC-MS (TIC)); C₁₈H₁₆F₇N,MW=379.32;

[0745] Mp: 95.4° C.

[0746] IR (NaCl): 1/λ (cm⁻¹)=2928, 1604, 1446, 1425, 1352, 1221, 1112,1059, 963, 763, 745, 702;

[0747]¹H-NMR (CDCl₃): δ (ppm)=7.36-7.20 (m, 5H, arom), 3.91 (t, 2H, CH₂,J=7.1), 3.28 (t, 2H, CH₂, J=20.0), 2.93 (t, 2H, CH₂, J=7.1), 2.47 (q,2H, CH₂, J=7.1), 2.21 (s, 3H, CH₃);

[0748] MS(EI, 70 eV): m/z (rel int. %)=379 (56); 210 (100); 211 (17);208 (13); 380 (12).

[0749] c)4-[2-(1,1,1,2,2,3,3-Heptafluoro-4-butyl)-3-methyl-6,7-dihydro-5H-pyrrolizin-1-yl]benzene-sulphonamide

[0750]2-(1,1,1,2,2,3,3-Heptafluoro-4-butyl)-3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizine(0.45 g, 77%, 1.1 mmol) is dissolved in CHCl₃ abs. (3 ml), the solutionis cooled to 0° C. and chlorosulphonic acid (0.66 ml, 1.15 g, 10 mmol)is slowly added dropwise. The mixture is heated for 2.5 h (58-61° C.)(TLC: SiO₂, ether-hexane 1:1, starting material Rf 0.8, sulphonic acidRf 0.0, chlorosulphonic acid Rf 0.5). The reaction mixture is quenchedon ice (20 ml), extracted 3 times with CHCl₃ (3×25 ml) and the collectedCHCl₃ solution is washed (30 ml of satd. NaCl solution), dried (Na₂SO₄sicc.) and concentrated (residue: 1.0 g). The chlorosulphonation product(1.0 g) is dissolved in THF abs. (10 ml) and conc. NH₄OH (25% strength,2,5 ml) is slowly added dropwise. The mixture is stirred at RT for 16 h,treated with semi-concentrated NH₄Cl solution (20 ml) and extracted 3times with ethyl acetate (3×50 ml). The washed (40 ml of satd. NaClsolution) ethyl acetate phase is dried (Na₂SO₄ sicc.) and concentrated.The residue (0.3 g) is separated on SiO₂ (30 g) using ether as aneluent: from fractions 3-6:0.15 g, (concentration 87%) and then washed2×with ether (0.5 ml) and dried: 0.09 g (90.2% according to HPLC)

[0751] Fractions 7-10:0.05 g (91.2% According to HPLC).

[0752] Y: 29.7%, (0.14 g, concentration 90.7%), C₁₈H₁₇F₇N₂O₂S, MW=458.4;

[0753] Mp: 220.7° C.

[0754] IR (NaCl): 1/λ (cm⁻¹)=3344, 3247, 1597, 1352, 1334, 1217, 1113,1053, 747, 545;

[0755]¹H-NMR (DMSO-d₆): δ (ppm)=7.89 and 7.39 (AA′BB′, 4H, arom, J=8.6),5.96 (s, 2H, NH₂), 3.93 (t, 2H, CH₂, J=7.0), 3.30 (t, 2H, CH₂, J=19.8),2.93 (t, 2H, CH₂, J=7.1), 2.53 (q, 2H, CH₂, J=7.1), 2.21 (s, 3H, CH₃).

[0756] The compound of Example 41 is prepared according to analogousprocedures.

[0757] Biological Activity

[0758] Test System for Determining the Inhibition of 5-lipoxygenase

[0759] Human granulocytes are used as a source of 5-lipoxygenase. LTB₄(leukotriene B₄) is formed from endogenous arachidonic acid bystimulation with calcium ionophore A 23187. The granulocytes areisolated and the enzyme reaction is carried out according to knownprocesses (see Arch. Pharm. 330, 307-312 (1997)).

[0760] The blood protected from clotting with heparin is centrifugedover a discontinuous Percoll®-gradient and the granulocyte layer ispipetted off. After lysis of the erythrocytes, the granulocytes arewashed repeatedly and then maintained at a specific cell count. Theenzyme reaction is then started with calcium ionophore A 23187 in thepresence or absence of the test substance after addition of Ca²⁺. Thesynthesis of the leukotrienes is stopped after 1.5 minutes. The samplesare centrifuged off and the supernatant is diluted. LTB₄ is determinedquantitatively by means of ELISA.

[0761] Test System for Determining the Inhibition of cyclooxygenase-1

[0762] In this test system, the amount of prostaglandin E₂ formed fromhuman platelets after addition of calcium ionophore is determined bymeans of ELISA. In this process, the platelets are obtained aftercentrifugation over a discontinuous Percoll® gradient. The enzymereaction and the determination of the metabolites formed is carried outin principle as in the case of the determination of the inhibition of5-lipoxygenase. Differences exist with respect to the incubation time.Furthermore, the addition of a thromboxane synthase inhibitor isnecessary (see Arch. Pharm. Med. Chem. 330, 307-312 (1997)).

[0763] Test System for Determining the Inhibition of cyclooxygenase-2

[0764] COX₂ (from placenta of sheep) is preincubated at 4° C. for 10 minwith test substance, then stimulated with arachidonic acid (5 μM) at 25°C. for 10 min. Diclofenac (IC₅₀(COX₂)=3.0×10⁻⁶ M) is used as areference. The determination is carried out in 3 dilutions (10⁻⁷, 10⁻⁶,10⁻⁵ M). The PGE₂ concentrations are quantified by means of ELISA (seeMitchell J. A, et al. Proc. Nat. Acad. Sci. 90: 11693-11697 (1993)).

1. [α]-Fused pyrrole compounds of the formula 1

in which X is CR8R9, S, O, NR12 or C(O); A is CR10R11 or a bond betweenX and the atom carrying the radicals R6 and R7; the first of theradicals R1, R2, R3 is 4-substituted phenyl, the substituent beingselected from C₁₋₄-alkylthio, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl,sulphamoyl, N—C₁₋₄-alkylsulphamoyl, N,N-di-C₁₋₄-alkylsulphamoyl,C₁₋₄-alkylsulphonamido or C₁₋₄-alkylsulphone-N—C₁₋₄-alkylamido; thesecond of the radicals R1, R2, R3 is C₁₋₆-alkyl which is optionallymono-, di- or tri- and, with halogen, also poly-substituted by identicalor different substituents selected from halogen, C₃₋₇-cycloalkyl,C₁₋₄-alkoxy, trifluoromethoxy, hydroxyl or trifluoromethyl,C₃₋₇-cycloalkyl which is optionally mono-, di- or tri- and, withhalogen, also poly-substituted by identical or different substituentsselected from halogen, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, C₃₋₇-cycloalkyl,C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy or hydroxyl, phenyl which is optionallymono-, di- or tri- and, with halogen, also poly-substituted by identicalor different substituents selected from halogen, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, C₁₋₄-alkylthio,hydroxyl, nitro, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, sulphamoyl,N—C₁₋₄-alkylsulphamoyl, N,N-di-C₁₋₄-alkylsulphamoyl,C₁₋₄-alkylsulphonamido or C₁₋₄-alkylsulphone-N—C₁₋₄-alkylamido; or anaromatic or non-aromatic mono- or bicyclic, optionally benzo-fused, 5-or 6-membered heterocyclic radical which contains 1, 2 or 3 heteroatomsindependently of one another selected from N, O and S and is optionallymono-, di- or tri- and, with halogen, also poly-substituted by identicalor different substituents selected from halogen, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, C₁₋₄-alkylthio,hydroxyl, nitro, C₁₋₄-alkylsulphinyl, C₁₋₄-alkylsulphonyl, sulphamoyl,N—C₁₋₄-alkylsulphamoyl, N,N-di-C₁₋₄-alkylsulphamoyl,C₁₋₄-alkylsulphonamido or C₁₋₄-alkylsulphone-N—C₁₋₄-alkylamido; thethird of the radicals R1, R2, R3 is H, C₁₋₆-alkyl, halo-C₁₋₄-alkyl,hydroxy-C₁₋₆-alkyl, —CHO, —COOH, —COCOOH, —COO—C₁₋₄-alkyl,—COO—C₁₄-Alkphenyl, —COCOO—C₁₋₄-alkyl, halogen, cyano,C₁₋₄-alkylsulphonyl, sulphamoyl or B—Y; in which B is C₁₋₈-alkylene orC₂₋₈-alkyenylene, each of which can optionally be substituted byhydroxyl or C₁₋₄-alkoxy; Y is —COOH, —COO—C₁₋₄-alkyl, —SO₃—C₁₋₄-alkyl,—CHO or hydroxyl; or the second and the third of the radicals R1, R2,R3, together with the C atoms to which they are bonded, are saturated orunsaturated C₃-C₇-cycloalkyl; R4-R11, which can be identical ordifferent, are hydrogen, C₁₋₆-alkyl, hydroxy-C₁₋₆-alkyl,C₁₋₄-alkoxy-C₁₋₆-alkyl, hydroxyl, COOH or acyloxy, where vicinalradicals can also represent bonds or geminal radicals, also togetherwith the C atom to which they are bonded, can represent carbonyl orC₃-C₇-Cycloalkyl; R12 is hydrogen, C₁₋₆-alkyl or phenyl, and opticalisomers, physiologically tolerable salts and physiologicallyhydrolysable esters thereof.
 2. Compounds according to claim 1, in whichX is CR8R9, A is a bond between X and the atom carrying the radicals R6and R7 and R4, R5, R6, R7, R8, R9, which can be identical or different,are hydrogen or CIA-alkyl.
 3. Compounds according to claim 1 or 2, inwhich the second of the radicals R1, R2, R3 is 4-substituted phenyl. 4.Compounds according to claim 3, in which the substituent is fluorine,methyl or trifluoromethyl.
 5. Compounds according to claim 1 or 2, inwhich the second of the radicals R1, R2, R3 is C₁₋₆-alkyl,C₃₋₇-cycloalkylmethyl or C₃₋₇-cycloalkyl.
 6. Compounds according toclaim 1 or 2, in which the second of the radicals R1, R2, R3 ispolyfluorinated C₁-alkyl, C₃₋₇-cycloalkylmethyl or C₃₋₇-cycloalkyl. 7.Compounds according to one of the preceding claims, in which the thirdof the radicals R1, R2, R3 is hydrogen, C₁₋₆-alkyl, CF₃ or halogen. 8.Compounds according to one of the preceding claims, in which the firstand the second of the radicals R1, R2, R3 are vicinal to one another. 9.Compounds according to one of the preceding claims, in which R1 is thefirst of the radicals R1, R2, R3.
 10. Pharmaceutical composition,comprising at least one compound according to one of claims 1 to 9, ifappropriate together with pharmaceutically acceptable excipients. 11.Use of at least one compound according to one of claims 1 to 9 for theproduction of a pharmaceutical composition for the treatment ofdisorders of the rheumatic type.